Skip to main content
SpringerLink
Log in

Proteinopathies: Deciphering Physiology and Mechanisms to Develop Effective Therapies for Neurodegenerative Diseases

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Neurodegenerative diseases (NDs) are a cluster of diseases marked by progressive neuronal loss, axonal transport blockage, mitochondrial dysfunction, oxidative stress, neuroinflammation, and aggregation of misfolded proteins. NDs are more prevalent beyond the age of 50, and their symptoms often include motor and cognitive impairment. Even though various proteins are involved in different NDs, the mechanisms of protein misfolding and aggregation are very similar. Recently, several studies have discovered that, like prions, these misfolded proteins have the inherent capability of translocation from one neuron to another, thus having far-reaching implications for understanding the processes involved in the onset and progression of NDs, as well as the development of innovative therapy and diagnostic options. These misfolded proteins can also influence the transcription of other proteins and form aggregates, tangles, plaques, and inclusion bodies, which then accumulate in the CNS, leading to neuronal dysfunction and neurodegeneration. This review demonstrates protein misfolding and aggregation in NDs, and similarities and differences between different protein aggregates have been discussed. Furthermore, we have also reviewed the disposal of protein aggregates, the various molecular machinery involved in the process, their regulation, and how these molecular mechanisms are targeted to build innovative therapeutic and diagnostic procedures. In addition, the landscape of various therapeutic interventions for targeting protein aggregation for the effective prevention or treatment of NDs has also been discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

Not applicable.

References

  1. Himalian R, Singh SK, Singh MP (2022) Ameliorative role of nutraceuticals on neurodegenerative diseases using the Drosophila melanogaster as a discovery model to define bioefficacy. J Am Nutr Assoc 41(5):511–539. https://doi.org/10.1080/07315724.2021.1904305

    Article  CAS  PubMed  Google Scholar 

  2. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42(3 Pt 1):631–639. https://doi.org/10.1212/wnl.42.3.631

    Article  CAS  PubMed  Google Scholar 

  3. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24(2):197–211. https://doi.org/10.1016/s0197-4580(02)00065-9

    Article  PubMed  Google Scholar 

  4. Coyne AN, Zaepfel BL, Zarnescu DC (2017) Failure to deliver and translate-new insights into RNA dysregulation in ALS. Front Cell Neurosci 11:243. https://doi.org/10.3389/fncel.2017.00243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. DeVos SL, Miller RL, Schoch KM, Holmes BB, Kebodeaux CS, Wegener AJ, Chen G, Shen T et al. (2017) Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med 9 (374). https://doi.org/10.1126/scitranslmed.aag0481

  6. Kritsilis M, S VR, Koutsoudaki PN, Evangelou K, Gorgoulis VG, Papadopoulos D (2018) Ageing, cellular senescence and neurodegenerative disease. Int J Mol Sci 19 (10). https://doi.org/10.3390/ijms19102937

  7. Aleksis R, Oleskovs F, Jaudzems K, Pahnke J, Biverstal H (2017) Structural studies of amyloid-beta peptides: unlocking the mechanism of aggregation and the associated toxicity. Biochimie 140:176–192. https://doi.org/10.1016/j.biochi.2017.07.011

    Article  CAS  PubMed  Google Scholar 

  8. Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (1989) Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3(4):519–526. https://doi.org/10.1016/0896-6273(89)90210-9

    Article  CAS  PubMed  Google Scholar 

  9. Guo Q, Bin H, Cheng J, Seefelder M, Engler T, Pfeifer G, Oeckl P, Otto M et al. (2018) The cryo-electron microscopy structure of huntingtin. Nature 555(7694):117–120. https://doi.org/10.1038/nature25502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pearce MMP, Spartz EJ, Hong W, Luo L, Kopito RR (2015) Prion-like transmission of neuronal huntingtin aggregates to phagocytic glia in the Drosophila brain. Nat Commun 6:6768. https://doi.org/10.1038/ncomms7768

    Article  CAS  PubMed  Google Scholar 

  11. Prasad A, Bharathi V, Sivalingam V, Girdhar A, Patel BK (2019) Molecular mechanisms of TDP-43 misfolding and pathology in amyotrophic lateral sclerosis. Front Mol Neurosci 12:25. https://doi.org/10.3389/fnmol.2019.00025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Falcon B, Zhang W, Schweighauser M, Murzin AG, Vidal R, Garringer HJ, Ghetti B, Scheres SHW et al. (2018) Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold. Acta Neuropathol 136(5):699–708. https://doi.org/10.1007/s00401-018-1914-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Muntane G, Dalfo E, Martinez A, Ferrer I (2008) Phosphorylation of tau and alpha-synuclein in synaptic-enriched fractions of the frontal cortex in Alzheimer’s disease, and in Parkinson’s disease and related alpha-synucleinopathies. Neuroscience 152(4):913–923. https://doi.org/10.1016/j.neuroscience.2008.01.030

    Article  CAS  PubMed  Google Scholar 

  14. Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 28:57–87. https://doi.org/10.1146/annurev.neuro.28.061604.135718

    Article  CAS  PubMed  Google Scholar 

  15. Bourdenx M, Koulakiotis NS, Sanoudou D, Bezard E, Dehay B, Tsarbopoulos A (2017) Protein aggregation and neurodegeneration in prototypical neurodegenerative diseases: examples of amyloidopathies, tauopathies and synucleinopathies. Prog Neurobiol 155:171–193. https://doi.org/10.1016/j.pneurobio.2015.07.003

    Article  CAS  PubMed  Google Scholar 

  16. Benilova I, Karran E, De Strooper B (2012) The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci 15(3):349–357. https://doi.org/10.1038/nn.3028

    Article  CAS  PubMed  Google Scholar 

  17. Castillo-Carranza DL, Gerson JE, Sengupta U, Guerrero-Munoz MJ, Lasagna-Reeves CA, Kayed R (2014) Specific targeting of tau oligomers in Htau mice prevents cognitive impairment and tau toxicity following injection with brain-derived tau oligomeric seeds. J Alzheimers Dis 40(Suppl 1):S97–S111. https://doi.org/10.3233/JAD-132477

    Article  CAS  PubMed  Google Scholar 

  18. Cohen TJ, Lee VM, Trojanowski JQ (2011) TDP-43 functions and pathogenic mechanisms implicated in TDP-43 proteinopathies. Trends Mol Med 17(11):659–667. https://doi.org/10.1016/j.molmed.2011.06.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ekimova IV, Plaksina DV, Pastukhov YF, Lapshina KV, Lazarev VF, Mikhaylova ER, Polonik SG, Pani B et al. (2018) New HSF1 inducer as a therapeutic agent in a rodent model of Parkinson’s disease. Exp Neurol 306:199–208. https://doi.org/10.1016/j.expneurol.2018.04.012

    Article  CAS  PubMed  Google Scholar 

  20. Buchberger A, Bukau B, Sommer T (2010) Protein quality control in the cytosol and the endoplasmic reticulum: brothers in arms. Mol Cell 40(2):238–252. https://doi.org/10.1016/j.molcel.2010.10.001

    Article  CAS  PubMed  Google Scholar 

  21. Neus Bosch M, Pugliese M, Andrade C, Gimeno-Bayon J, Mahy N, Rodriguez MJ (2015) Amyloid-beta immunotherapy reduces amyloid plaques and astroglial reaction in aged domestic dogs. Neurodegener Dis 15(1):24–37. https://doi.org/10.1159/000368672

    Article  CAS  PubMed  Google Scholar 

  22. Xing HY, Li B, Peng D, Wang CY, Wang GY, Li P, Le YY, Wang JM et al. (2017) A novel monoclonal antibody against the N-terminus of Abeta1-42 reduces plaques and improves cognition in a mouse model of Alzheimer’s disease. PLoS ONE 12(6):e0180076. https://doi.org/10.1371/journal.pone.0180076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schenk DB, Koller M, Ness DK, Griffith SG, Grundman M, Zago W, Soto J, Atiee G, Ostrowitzki S, Kinney GG (2017) First-in-human assessment of PRX002, an anti-alpha-synuclein monoclonal antibody, in healthy volunteers. Mov Disord 32(2):211–218. https://doi.org/10.1002/mds.26878

    Article  CAS  PubMed  Google Scholar 

  24. Silveira CRA, MacKinley J, Coleman K, Li Z, Finger E, Bartha R, Morrow SA, Wells J et al. (2019) Ambroxol as a novel disease-modifying treatment for Parkinson’s disease dementia: protocol for a single-centre, randomized, double-blind, placebo-controlled trial. BMC Neurol 19(1):20. https://doi.org/10.1186/s12883-019-1252-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Qu J, Ren X, Xue F, He Y, Zhang R, Zheng Y, Huang H, Wang W et al. (2020) Specific knockdown of alpha-synuclein by peptide-directed proteasome degradation rescued its associated neurotoxicity. Cell Chem Biol 27(6):751-762 e754. https://doi.org/10.1016/j.chembiol.2020.03.010

    Article  CAS  PubMed  Google Scholar 

  26. McFarthing K, Simuni T (2019) Clinical trial highlights: targetting alpha-synuclein. J Parkinsons Dis 9(1):5–16. https://doi.org/10.3233/JPD-189004

    Article  PubMed  Google Scholar 

  27. Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, Hager K, Andreasen N et al. (2018) Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 378(4):321–330. https://doi.org/10.1056/NEJMoa1705971

    Article  CAS  PubMed  Google Scholar 

  28. Sweeney P, Park H, Baumann M, Dunlop J, Frydman J, Kopito R, McCampbell A, Leblanc G et al. (2017) Protein misfolding in neurodegenerative diseases: implications and strategies. Transl Neurodegener 6:6. https://doi.org/10.1186/s40035-017-0077-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gurry T, Stultz CM (2014) Mechanism of amyloid-beta fibril elongation. Biochemistry 53(44):6981–6991. https://doi.org/10.1021/bi500695g

    Article  CAS  PubMed  Google Scholar 

  30. Yang PH, Zhu JX, Huang YD, Zhang XY, Lei P, Bush AI, Xiang Q, Su ZJ et al. (2016) Human basic fibroblast growth factor inhibits tau phosphorylation via the PI3K/Akt-GSK3beta signaling pathway in a 6-hydroxydopamine-induced model of Parkinson’s disease. Neurodegener Dis 16(5–6):357–369. https://doi.org/10.1159/000445871

    Article  CAS  PubMed  Google Scholar 

  31. Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2(7):492–501. https://doi.org/10.1038/35081564

    Article  CAS  PubMed  Google Scholar 

  32. Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 33(1):95–130. https://doi.org/10.1016/s0165-0173(00)00019-9

    Article  CAS  PubMed  Google Scholar 

  33. Spillantini MG, Goedert M (2013) Tau pathology and neurodegeneration. Lancet Neurol 12(6):609–622. https://doi.org/10.1016/S1474-4422(13)70090-5

    Article  CAS  PubMed  Google Scholar 

  34. Sanghai N, Tranmer GK (2021) Hydrogen peroxide and amyotrophic lateral sclerosis: from biochemistry to pathophysiology. Antioxidants (Basel) 11 (1). https://doi.org/10.3390/antiox11010052

  35. Koyuncu S, Fatima A, Gutierrez-Garcia R, Vilchez D (2017) Proteostasis of huntingtin in health and disease. Int J Mol Sci 18 (7). https://doi.org/10.3390/ijms18071568

  36. Baldwin KJ, Correll CM (2019) Prion disease. Semin Neurol 39(4):428–439. https://doi.org/10.1055/s-0039-1687841

    Article  PubMed  Google Scholar 

  37. DeTure MA, Dickson DW (2019) The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener 14(1):32. https://doi.org/10.1186/s13024-019-0333-5

    Article  PubMed  PubMed Central  Google Scholar 

  38. Rajasekhar K, Chakrabarti M, Govindaraju T (2015) Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer’s disease. Chem Commun (Camb) 51(70):13434–13450. https://doi.org/10.1039/c5cc05264e

    Article  CAS  Google Scholar 

  39. Pampuscenko K, Morkuniene R, Sneideris T, Smirnovas V, Budvytyte R, Valincius G, Brown GC, Borutaite V (2020) Extracellular tau induces microglial phagocytosis of living neurons in cell cultures. J Neurochem 154(3):316–329. https://doi.org/10.1111/jnc.14940

    Article  CAS  PubMed  Google Scholar 

  40. Butterfield DA, Swomley AM, Sultana R (2013) Amyloid beta-peptide (1–42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression. Antioxid Redox Signal 19(8):823–835. https://doi.org/10.1089/ars.2012.5027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Oliveira LF, Rodrigues LD, Cardillo GM, Nejm MB, Guimaraes-Marques M, Reyes-Garcia SZ, Zuqui K, Vassallo DV et al. (2020) Deleterious effects of chronic mercury exposure on in vitro LTP, memory process, and oxidative stress. Environ Sci Pollut Res Int 27(7):7559–7569. https://doi.org/10.1007/s11356-019-06625-6

    Article  CAS  PubMed  Google Scholar 

  42. He Y, Yao PF, Chen SB, Huang ZH, Huang SL, Tan JH, Li D, Gu LQ et al. (2013) Synthesis and evaluation of 7,8-dehydrorutaecarpine derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 63:299–312. https://doi.org/10.1016/j.ejmech.2013.02.014

    Article  CAS  PubMed  Google Scholar 

  43. Nimmrich V, Ebert U (2009) Is Alzheimer’s disease a result of presynaptic failure? Synaptic dysfunctions induced by oligomeric beta-amyloid. Rev Neurosci 20(1):1–12. https://doi.org/10.1515/revneuro.2009.20.1.1

    Article  CAS  PubMed  Google Scholar 

  44. Nesi G, Sestito S, Digiacomo M, Rapposelli S (2017) Oxidative stress, mitochondrial abnormalities and proteins deposition: multitarget approaches in Alzheimer’s disease. Curr Top Med Chem 17(27):3062–3079. https://doi.org/10.2174/1568026617666170607114232

    Article  CAS  PubMed  Google Scholar 

  45. Shi C, Zhu X, Wang J, Long D (2014) Intromitochondrial IkappaB/NF-kappaB signaling pathway is involved in amyloid beta peptide-induced mitochondrial dysfunction. J Bioenerg Biomembr 46(5):371–376. https://doi.org/10.1007/s10863-014-9567-7

    Article  CAS  PubMed  Google Scholar 

  46. Sivandzade F, Prasad S, Bhalerao A, Cucullo L (2019) NRF2 and NF-B interplay in cerebrovascular and neurodegenerative disorders: molecular mechanisms and possible therapeutic approaches. Redox Biol 21:101059. https://doi.org/10.1016/j.redox.2018.11.017

    Article  CAS  PubMed  Google Scholar 

  47. Sisodia SS, Koo EH, Hoffman PN, Perry G, Price DL (1993) Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system. J Neurosci 13(7):3136–3142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Estus S, Golde TE, Kunishita T, Blades D, Lowery D, Eisen M, Usiak M, Qu XM et al. (1992) Potentially amyloidogenic, carboxyl-terminal derivatives of the amyloid protein precursor. Science 255(5045):726–728. https://doi.org/10.1126/science.1738846

    Article  CAS  PubMed  Google Scholar 

  49. Naslund J, Jensen M, Tjernberg LO, Thyberg J, Terenius L, Nordstedt C (1994) The metabolic pathway generating p3, an A beta-peptide fragment, is probably non-amyloidogenic. Biochem Biophys Res Commun 204(2):780–787. https://doi.org/10.1006/bbrc.1994.2527

    Article  CAS  PubMed  Google Scholar 

  50. Giuffrida ML, Caraci F, De Bona P, Pappalardo G, Nicoletti F, Rizzarelli E, Copani A (2010) The monomer state of beta-amyloid: where the Alzheimer’s disease protein meets physiology. Rev Neurosci 21(2):83–93. https://doi.org/10.1515/revneuro.2010.21.2.83

    Article  CAS  PubMed  Google Scholar 

  51. Kollmer M, Close W, Funk L, Rasmussen J, Bsoul A, Schierhorn A, Schmidt M, Sigurdson CJ et al. (2019) Cryo-EM structure and polymorphism of Abeta amyloid fibrils purified from Alzheimer’s brain tissue. Nat Commun 10(1):4760. https://doi.org/10.1038/s41467-019-12683-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Fitzpatrick AW, Saibil HR (2019) Cryo-EM of amyloid fibrils and cellular aggregates. Curr Opin Struct Biol 58:34–42. https://doi.org/10.1016/j.sbi.2019.05.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cohen SI, Linse S, Luheshi LM, Hellstrand E, White DA, Rajah L, Otzen DE, Vendruscolo M et al. (2013) Proliferation of amyloid-beta42 aggregates occurs through a secondary nucleation mechanism. Proc Natl Acad Sci U S A 110(24):9758–9763. https://doi.org/10.1073/pnas.1218402110

    Article  PubMed  PubMed Central  Google Scholar 

  54. Wang Y, Martinez-Vicente M, Kruger U, Kaushik S, Wong E, Mandelkow EM, Cuervo AM, Mandelkow E (2009) Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet 18(21):4153–4170. https://doi.org/10.1093/hmg/ddp367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wolfing H, Chieng BC et al. (2010) Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142(3):387–397. https://doi.org/10.1016/j.cell.2010.06.036

    Article  CAS  PubMed  Google Scholar 

  56. Iwata M, Watanabe S, Yamane A, Miyasaka T, Misonou H (2019) Regulatory mechanisms for the axonal localization of tau protein in neurons. Mol Biol Cell 30(19):2441–2457. https://doi.org/10.1091/mbc.E19-03-0183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ramsden M, Kotilinek L, Forster C, Paulson J, McGowan E, SantaCruz K, Guimaraes A, Yue M et al. (2005) Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci 25(46):10637–10647. https://doi.org/10.1523/JNEUROSCI.3279-05.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jiao SS, Shen LL, Zhu C, Bu XL, Liu YH, Liu CH, Yao XQ, Zhang LL et al. (2016) Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer’s disease. Transl Psychiatry 6(10):e907. https://doi.org/10.1038/tp.2016.186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Schweers O, Schonbrunn-Hanebeck E, Marx A, Mandelkow E (1994) Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure. J Biol Chem 269(39):24290–24297

    Article  CAS  PubMed  Google Scholar 

  60. Goedert M, Falcon B, Zhang W, Ghetti B, Scheres SHW (2018) Distinct conformers of assembled tau in Alzheimer’s and Pick’s diseases. Cold Spring Harb Symp Quant Biol 83:163–171. https://doi.org/10.1101/sqb.2018.83.037580

    Article  PubMed  Google Scholar 

  61. Hisanaga SI, Krishnankutty A, Kimura T (2022) In vivo analysis of the phosphorylation of tau and the tau protein kinases Cdk5-p35 and GSK3beta by using Phos-tag SDS-PAGE. J Proteomics 262:104591. https://doi.org/10.1016/j.jprot.2022.104591

    Article  CAS  PubMed  Google Scholar 

  62. Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K (2013) Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J Alzheimers Dis 33(Suppl 1):S123-139. https://doi.org/10.3233/JAD-2012-129031

    Article  CAS  PubMed  Google Scholar 

  63. Lei P, Ayton S, Finkelstein DI, Adlard PA, Masters CL, Bush AI (2010) Tau protein: relevance to Parkinson’s disease. Int J Biochem Cell Biol 42(11):1775–1778. https://doi.org/10.1016/j.biocel.2010.07.016

    Article  CAS  PubMed  Google Scholar 

  64. Fernandez-Nogales M, Cabrera JR, Santos-Galindo M, Hoozemans JJ, Ferrer I, Rozemuller AJ, Hernandez F, Avila J et al. (2014) Huntington’s disease is a four-repeat tauopathy with tau nuclear rods. Nat Med 20(8):881–885. https://doi.org/10.1038/nm.3617

    Article  CAS  PubMed  Google Scholar 

  65. Cisbani G, Maxan A, Kordower JH, Planel E, Freeman TB, Cicchetti F (2017) Presence of tau pathology within foetal neural allografts in patients with Huntington’s and Parkinson’s disease. Brain 140(11):2982–2992. https://doi.org/10.1093/brain/awx255

    Article  PubMed  PubMed Central  Google Scholar 

  66. Shi Y, Manis M, Long J, Wang K, Sullivan PM, Remolina Serrano J, Hoyle R, Holtzman DM (2019) Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med 216(11):2546–2561. https://doi.org/10.1084/jem.20190980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Pascoal TA, Benedet AL, Ashton NJ, Kang MS, Therriault J, Chamoun M, Savard M, Lussier FZ et al. (2021) Microglial activation and tau propagate jointly across Braak stages. Nat Med 27(9):1592–1599. https://doi.org/10.1038/s41591-021-01456-w

    Article  CAS  PubMed  Google Scholar 

  68. Burmann BM, Gerez JA, Matecko-Burmann I, Campioni S, Kumari P, Ghosh D, Mazur A, Aspholm EE et al. (2020) Regulation of alpha-synuclein by chaperones in mammalian cells. Nature 577(7788):127–132. https://doi.org/10.1038/s41586-019-1808-9

    Article  CAS  PubMed  Google Scholar 

  69. Schweighauser M, Shi Y, Tarutani A, Kametani F, Murzin AG, Ghetti B, Matsubara T, Tomita T et al. (2020) Structures of alpha-synuclein filaments from multiple system atrophy. Nature 585(7825):464–469. https://doi.org/10.1038/s41586-020-2317-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Flynn JD, McGlinchey RP, Walker RL 3rd, Lee JC (2018) Structural features of alpha-synuclein amyloid fibrils revealed by Raman spectroscopy. J Biol Chem 293(3):767–776. https://doi.org/10.1074/jbc.M117.812388

    Article  CAS  PubMed  Google Scholar 

  71. Greenbau EA, Graves CL, Mishizen-Eberz AJ, Lupoli MA, Lynch DR, Englander SW, Axelsen PH, Giasson BI (2005) The E46K mutation in alpha-synuclein increases amyloid fibril formation. J Biol Chem 280(9):7800–7807. https://doi.org/10.1074/jbc.M411638200

    Article  CAS  Google Scholar 

  72. Conway KA, Harper JD, Lansbury PT Jr (2000) Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to Parkinson’s disease are typical amyloid. Biochemistry 39(10):2552–2563. https://doi.org/10.1021/bi991447r

    Article  CAS  PubMed  Google Scholar 

  73. Fares MB, Jagannath S, Lashuel HA (2021) Reverse engineering Lewy bodies: how far have we come and how far can we go? Nat Rev Neurosci 22(2):111–131. https://doi.org/10.1038/s41583-020-00416-6

    Article  CAS  PubMed  Google Scholar 

  74. Uversky VN, Li J, Fink AL (2001) Evidence for a partially folded intermediate in alpha-synuclein fibril formation. J Biol Chem 276(14):10737–10744. https://doi.org/10.1074/jbc.M010907200

    Article  CAS  PubMed  Google Scholar 

  75. Bandopadhyay R, de Belleroche J (2010) Pathogenesis of Parkinson’s disease: emerging role of molecular chaperones. Trends Mol Med 16(1):27–36. https://doi.org/10.1016/j.molmed.2009.11.004

    Article  CAS  PubMed  Google Scholar 

  76. Bartels T, Choi JG, Selkoe DJ (2011) alpha-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477(7362):107–110. https://doi.org/10.1038/nature10324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Burre J, Vivona S, Diao J, Sharma M, Brunger AT, Sudhof TC (2013) Properties of native brain alpha-synuclein. Nature 498 (7453):E4–6; discussion E6–7. https://doi.org/10.1038/nature12125

  78. Pfefferkorn CM, Lee JC (2010) Tryptophan probes at the alpha-synuclein and membrane interface. J Phys Chem B 114(13):4615–4622. https://doi.org/10.1021/jp908092e

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Costanzo M, Abounit S, Marzo L, Danckaert A, Chamoun Z, Roux P, Zurzolo C (2013) Transfer of polyglutamine aggregates in neuronal cells occurs in tunneling nanotubes. J Cell Sci 126(Pt 16):3678–3685. https://doi.org/10.1242/jcs.126086

    Article  CAS  PubMed  Google Scholar 

  80. Victoria GS, Zurzolo C (2017) The spread of prion-like proteins by lysosomes and tunneling nanotubes: implications for neurodegenerative diseases. J Cell Biol 216(9):2633–2644. https://doi.org/10.1083/jcb.201701047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Aiken CT, Steffan JS, Guerrero CM, Khashwji H, Lukacsovich T, Simmons D, Purcell JM, Menhaji K et al. (2009) Phosphorylation of threonine 3: implications for huntingtin aggregation and neurotoxicity. J Biol Chem 284(43):29427–29436. https://doi.org/10.1074/jbc.M109.013193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Gu X, Greiner ER, Mishra R, Kodali R, Osmand A, Finkbeiner S, Steffan JS, Thompson LM et al. (2009) Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice. Neuron 64(6):828–840. https://doi.org/10.1016/j.neuron.2009.11.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Chaibva M, Jawahery S, Pilkington AWT, Arndt JR, Sarver O, Valentine S, Matysiak S, Legleiter J (2016) Acetylation within the first 17 residues of huntingtin exon 1 alters aggregation and lipid binding. Biophys J 111(2):349–362. https://doi.org/10.1016/j.bpj.2016.06.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K et al. (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351(3):602–611. https://doi.org/10.1016/j.bbrc.2006.10.093

    Article  CAS  PubMed  Google Scholar 

  85. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T et al. (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314(5796):130–133. https://doi.org/10.1126/science.1134108

    Article  CAS  PubMed  Google Scholar 

  86. Ayala YM, Zago P, D’Ambrogio A, Xu YF, Petrucelli L, Buratti E, Baralle FE (2008) Structural determinants of the cellular localization and shuttling of TDP-43. J Cell Sci 121(Pt 22):3778–3785. https://doi.org/10.1242/jcs.038950

    Article  CAS  PubMed  Google Scholar 

  87. Lukavsky PJ, Daujotyte D, Tollervey JR, Ule J, Stuani C, Buratti E, Baralle FE, Damberger FF et al. (2013) Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43. Nat Struct Mol Biol 20(12):1443–1449. https://doi.org/10.1038/nsmb.2698

    Article  CAS  PubMed  Google Scholar 

  88. Mompean M, Romano V, Pantoja-Uceda D, Stuani C, Baralle FE, Buratti E, Laurents DV (2016) The TDP-43 N-terminal domain structure at high resolution. FEBS J 283(7):1242–1260. https://doi.org/10.1111/febs.13651

    Article  CAS  PubMed  Google Scholar 

  89. Kuo PH, Chiang CH, Wang YT, Doudeva LG, Yuan HS (2014) The crystal structure of TDP-43 RRM1-DNA complex reveals the specific recognition for UG- and TG-rich nucleic acids. Nucleic Acids Res 42(7):4712–4722. https://doi.org/10.1093/nar/gkt1407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Prusiner SB (2013) Biology and genetics of prions causing neurodegeneration. Annu Rev Genet 47:601–623. https://doi.org/10.1146/annurev-genet-110711-155524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Pignataro A, Middei S (2017) Trans-synaptic spread of amyloid-beta in Alzheimer’s disease: paths to beta-amyloidosis. Neural Plast 2017:5281829. https://doi.org/10.1155/2017/5281829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ariazi J, Benowitz A, De Biasi V, Den Boer ML, Cherqui S, Cui H, Douillet N, Eugenin EA et al. (2017) Tunneling nanotubes and gap junctions-their role in long-range intercellular communication during development, health, and disease conditions. Front Mol Neurosci 10:333. https://doi.org/10.3389/fnmol.2017.00333

    Article  PubMed  PubMed Central  Google Scholar 

  93. Kelly JW (1998) The environmental dependency of protein folding best explains prion and amyloid diseases. Proc Natl Acad Sci U S A 95(3):930–932. https://doi.org/10.1073/pnas.95.3.930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Marrero-Winkens C, Sankaran C, Schatzl HM (2020) From seeds to fibrils and back: fragmentation as an overlooked step in the propagation of prions and prion-like proteins. Biomolecules 10 (9). https://doi.org/10.3390/biom10091305

  95. Wu JW, Herman M, Liu L, Simoes S, Acker CM, Figueroa H, Steinberg JI, Margittai M et al. (2013) Small misfolded Tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J Biol Chem 288(3):1856–1870. https://doi.org/10.1074/jbc.M112.394528

    Article  CAS  PubMed  Google Scholar 

  96. Reyes JF, Rey NL, Bousset L, Melki R, Brundin P, Angot E (2014) Alpha-synuclein transfers from neurons to oligodendrocytes. Glia 62(3):387–398. https://doi.org/10.1002/glia.22611

    Article  PubMed  Google Scholar 

  97. Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A, Barker SJ, Foley AC et al. (2014) Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82(6):1271–1288. https://doi.org/10.1016/j.neuron.2014.04.047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Nath S, Agholme L, Kurudenkandy FR, Granseth B, Marcusson J, Hallbeck M (2012) Spreading of neurodegenerative pathology via neuron-to-neuron transmission of beta-amyloid. J Neurosci 32(26):8767–8777. https://doi.org/10.1523/JNEUROSCI.0615-12.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Jackson RJ, Rudinskiy N, Herrmann AG, Croft S, Kim JM, Petrova V, Ramos-Rodriguez JJ, Pitstick R et al. (2016) Human tau increases amyloid beta plaque size but not amyloid beta-mediated synapse loss in a novel mouse model of Alzheimer’s disease. Eur J Neurosci 44(12):3056–3066. https://doi.org/10.1111/ejn.13442

    Article  PubMed  PubMed Central  Google Scholar 

  100. Smith HL, Mallucci GR (2016) The unfolded protein response: mechanisms and therapy of neurodegeneration. Brain 139(Pt 8):2113–2121. https://doi.org/10.1093/brain/aww101

    Article  PubMed  PubMed Central  Google Scholar 

  101. Shimura H, Schwartz D, Gygi SP, Kosik KS (2004) CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. J Biol Chem 279(6):4869–4876. https://doi.org/10.1074/jbc.M305838200

    Article  CAS  PubMed  Google Scholar 

  102. Kohler C, Dinekov M, Gotz J (2014) Granulovacuolar degeneration and unfolded protein response in mouse models of tauopathy and Abeta amyloidosis. Neurobiol Dis 71:169–179. https://doi.org/10.1016/j.nbd.2014.07.006

    Article  CAS  PubMed  Google Scholar 

  103. Mayer M, Kies U, Kammermeier R, Buchner J (2000) BiP and PDI cooperate in the oxidative folding of antibodies in vitro. J Biol Chem 275(38):29421–29425. https://doi.org/10.1074/jbc.M002655200

    Article  CAS  PubMed  Google Scholar 

  104. Hoozemans JJ, Veerhuis R, Van Haastert ES, Rozemuller JM, Baas F, Eikelenboom P, Scheper W (2005) The unfolded protein response is activated in Alzheimer’s disease. Acta Neuropathol 110(2):165–172. https://doi.org/10.1007/s00401-005-1038-0

    Article  CAS  PubMed  Google Scholar 

  105. Rozpedek W, Pytel D, Mucha B, Leszczynska H, Diehl JA, Majsterek I (2016) The role of the PERK/eIF2alpha/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Curr Mol Med 16(6):533–544. https://doi.org/10.2174/1566524016666160523143937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Thorpe JA, Schwarze SR (2010) IRE1alpha controls cyclin A1 expression and promotes cell proliferation through XBP-1. Cell Stress Chaperones 15(5):497–508. https://doi.org/10.1007/s12192-009-0163-4

    Article  CAS  PubMed  Google Scholar 

  107. Duran-Aniotz C, Cornejo VH, Espinoza S, Ardiles AO, Medinas DB, Salazar C, Foley A, Gajardo I et al. (2017) IRE1 signaling exacerbates Alzheimer’s disease pathogenesis. Acta Neuropathol 134(3):489–506. https://doi.org/10.1007/s00401-017-1694-x

    Article  CAS  PubMed  Google Scholar 

  108. Tam AB, Roberts LS, Chandra V, Rivera IG, Nomura DK, Forbes DJ, Niwa M (2018) The UPR activator ATF6 responds to proteotoxic and lipotoxic stress by distinct mechanisms. Dev Cell 46(3):327-343 e327. https://doi.org/10.1016/j.devcel.2018.04.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Patwardhan A, Cheng N, Trejo J (2021) Post-translational modifications of G protein-coupled receptors control cellular signaling dynamics in space and time. Pharmacol Rev 73(1):120–151. https://doi.org/10.1124/pharmrev.120.000082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Babu JR, Geetha T, Wooten MW (2005) Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J Neurochem 94(1):192–203. https://doi.org/10.1111/j.1471-4159.2005.03181.x

    Article  CAS  PubMed  Google Scholar 

  111. Ikeda K, Akiyama H, Arai T, Kondo H, Haga C, Iritani S, Tsuchiya K (1998) Alz-50/Gallyas-positive lysosome-like intraneuronal granules in Alzheimer’s disease and control brains. Neurosci Lett 258(2):113–116. https://doi.org/10.1016/s0304-3940(98)00867-2

    Article  CAS  PubMed  Google Scholar 

  112. Choi I, Zhang Y, Seegobin SP, Pruvost M, Wang Q, Purtell K, Zhang B, Yue Z (2020) Microglia clear neuron-released alpha-synuclein via selective autophagy and prevent neurodegeneration. Nat Commun 11(1):1386. https://doi.org/10.1038/s41467-020-15119-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Sun L, Lian Y, Ding J, Meng Y, Li C, Chen L, Qiu P (2019) The role of chaperone-mediated autophagy in neurotoxicity induced by alpha-synuclein after methamphetamine exposure. Brain Behav 9(8):e01352. https://doi.org/10.1002/brb3.1352

    Article  PubMed  PubMed Central  Google Scholar 

  114. Behnke J, Mann MJ, Scruggs FL, Feige MJ, Hendershot LM (2016) Members of the Hsp70 family recognize distinct types of sequences to execute ER quality control. Mol Cell 63(5):739–752. https://doi.org/10.1016/j.molcel.2016.07.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Agashe VR, Hartl FU (2000) Roles of molecular chaperones in cytoplasmic protein folding. Semin Cell Dev Biol 11(1):15–25. https://doi.org/10.1006/scdb.1999.0347

    Article  CAS  PubMed  Google Scholar 

  116. Arhar T, Shkedi A, Nadel CM, Gestwicki JE (2021) The interactions of molecular chaperones with client proteins: why are they so weak? J Biol Chem 297(5):101282. https://doi.org/10.1016/j.jbc.2021.101282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. He WT, Xue W, Gao YG, Hong JY, Yue HW, Jiang LL, Hu HY (2017) HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP19. Sci Rep 7(1):14797. https://doi.org/10.1038/s41598-017-13711-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Zhang M, Qian C, Zheng ZG, Qian F, Wang Y, Thu PM, Zhang X, Zhou Y et al. (2018) Jujuboside A promotes Abeta clearance and ameliorates cognitive deficiency in Alzheimer’s disease through activating Axl/HSP90/PPARgamma pathway. Theranostics 8(15):4262–4278. https://doi.org/10.7150/thno.26164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Robinson MB, Tidwell JL, Gould T, Taylor AR, Newbern JM, Graves J, Tytell M, Milligan CE (2005) Extracellular heat shock protein 70: a critical component for motoneuron survival. J Neurosci 25(42):9735–9745. https://doi.org/10.1523/JNEUROSCI.1912-05.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Lyon MS, Milligan C (2019) Extracellular heat shock proteins in neurodegenerative diseases: new perspectives. Neurosci Lett 711:134462. https://doi.org/10.1016/j.neulet.2019.134462

    Article  CAS  PubMed  Google Scholar 

  121. Magen D, Georgopoulos C, Bross P, Ang D, Segev Y, Goldsher D, Nemirovski A, Shahar E et al. (2008) Mitochondrial hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy. Am J Hum Genet 83(1):30–42. https://doi.org/10.1016/j.ajhg.2008.05.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Biebl MM, Buchner J (2019) Structure, function, and regulation of the Hsp90 machinery. Cold Spring Harb Perspect Biol 11 (9). https://doi.org/10.1101/cshperspect.a034017

  123. Bohush A, Niewiadomska G, Weis S, Filipek A (2019) HSP90 and its novel co-chaperones, SGT1 and CHP-1, in brain of patients with Parkinson’s disease and dementia with Lewy bodies. J Parkinsons Dis 9(1):97–107. https://doi.org/10.3233/JPD-181443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Soti C, Csermely P (2002) Chaperones and aging: role in neurodegeneration and in other civilizational diseases. Neurochem Int 41(6):383–389. https://doi.org/10.1016/s0197-0186(02)00043-8

    Article  CAS  PubMed  Google Scholar 

  125. Abisambra JF, Blair LJ, Hill SE, Jones JR, Kraft C, Rogers J, Koren J 3rd, Jinwal UK et al. (2010) Phosphorylation dynamics regulate Hsp27-mediated rescue of neuronal plasticity deficits in tau transgenic mice. J Neurosci 30(46):15374–15382. https://doi.org/10.1523/JNEUROSCI.3155-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Selig EE, Zlatic CO, Cox D, Mok YF, Gooley PR, Ecroyd H, Griffin MDW (2020) N- and C-terminal regions of alphaB-crystallin and Hsp27 mediate inhibition of amyloid nucleation, fibril binding, and fibril disaggregation. J Biol Chem 295(29):9838–9854. https://doi.org/10.1074/jbc.RA120.012748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Outeiro TF, Klucken J, Strathearn KE, Liu F, Nguyen P, Rochet JC, Hyman BT, McLean PJ (2006) Small heat shock proteins protect against alpha-synuclein-induced toxicity and aggregation. Biochem Biophys Res Commun 351(3):631–638. https://doi.org/10.1016/j.bbrc.2006.10.085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Goldfarb SB, Kashlan OB, Watkins JN, Suaud L, Yan W, Kleyman TR, Rubenstein RC (2006) Differential effects of Hsc70 and Hsp70 on the intracellular trafficking and functional expression of epithelial sodium channels. Proc Natl Acad Sci U S A 103(15):5817–5822. https://doi.org/10.1073/pnas.0507903103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Brandvold KR, Morimoto RI (2015) The chemical biology of molecular chaperones–implications for modulation of proteostasis. J Mol Biol 427(18):2931–2947. https://doi.org/10.1016/j.jmb.2015.05.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Xu H (2018) Cochaperones enable Hsp70 to use ATP energy to stabilize native proteins out of the folding equilibrium. Sci Rep 8(1):13213. https://doi.org/10.1038/s41598-018-31641-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Li H, Yang J, Wang Y, Liu Q, Cheng J, Wang F (2019) Neuroprotective effects of increasing levels of HSP70 against neuroinflammation in Parkinson’s disease model by inhibition of NF-kappaB and STAT3. Life Sci 234:116747. https://doi.org/10.1016/j.lfs.2019.116747

    Article  CAS  PubMed  Google Scholar 

  132. Zheng Q, Huang C, Guo J, Tan J, Wang C, Tang B, Zhang H (2018) Hsp70 participates in PINK1-mediated mitophagy by regulating the stability of PINK1. Neurosci Lett 662:264–270. https://doi.org/10.1016/j.neulet.2017.10.051

    Article  CAS  PubMed  Google Scholar 

  133. Evgen’ev M, Bobkova N, Krasnov G, Garbuz D, Funikov S, Kudryavtseva A, Kulikov A, Samokhin A et al. (2019) The effect of human HSP70 administration on a mouse model of Alzheimer’s disease strongly depends on transgenicity and age. J Alzheimers Dis 67(4):1391–1404. https://doi.org/10.3233/JAD-180987

    Article  CAS  PubMed  Google Scholar 

  134. Chen JY, Parekh M, Seliman H, Bakshinskaya D, Dai W, Kwan K, Chen KY, Liu AYC (2018) Heat shock promotes inclusion body formation of mutant huntingtin (mHtt) and alleviates mHtt-induced transcription factor dysfunction. J Biol Chem 293(40):15581–15593. https://doi.org/10.1074/jbc.RA118.002933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Csermely P, Kajtar J, Hollosi M, Jalsovszky G, Holly S, Kahn CR, Gergely P Jr, Soti C et al. (1993) ATP induces a conformational change of the 90-kDa heat shock protein (hsp90). J Biol Chem 268(3):1901–1907

    Article  CAS  PubMed  Google Scholar 

  136. Obermann WM, Sondermann H, Russo AA, Pavletich NP, Hartl FU (1998) In vivo function of Hsp90 is dependent on ATP binding and ATP hydrolysis. J Cell Biol 143(4):901–910. https://doi.org/10.1083/jcb.143.4.901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ernst JT, Neubert T, Liu M, Sperry S, Zuccola H, Turnbull A, Fleck B, Kargo W et al. (2014) Identification of novel HSP90alpha/beta isoform selective inhibitors using structure-based drug design. Demonstration of potential utility in treating CNS disorders such as Huntington’s disease. J Med Chem 57(8):3382–3400. https://doi.org/10.1021/jm500042s

    Article  CAS  PubMed  Google Scholar 

  138. Rane A, Rajagopalan S, Ahuja M, Thomas B, Chinta SJ, Andersen JK (2018) Hsp90 co-chaperone p23 contributes to dopaminergic mitochondrial stress via stabilization of PHD2: implications for Parkinson’s disease. Neurotoxicology 65:166–173. https://doi.org/10.1016/j.neuro.2018.02.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Janowska MK, Baughman HER, Woods CN, Klevit RE (2019) Mechanisms of small heat shock proteins. Cold Spring Harb Perspect Biol 11 (10). https://doi.org/10.1101/cshperspect.a034025

  140. Vicente Miranda H, Chegao A, Oliveira MS, Fernandes Gomes B, Enguita FJ, Outeiro TF (2020) Hsp27 reduces glycation-induced toxicity and aggregation of alpha-synuclein. FASEB J 34(5):6718–6728. https://doi.org/10.1096/fj.201902936R

    Article  CAS  PubMed  Google Scholar 

  141. Lavoie JN, Hickey E, Weber LA, Landry J (1993) Modulation of actin microfilament dynamics and fluid phase pinocytosis by phosphorylation of heat shock protein 27. J Biol Chem 268(32):24210–24214

    Article  CAS  PubMed  Google Scholar 

  142. Gonzales SJ, Reyes RA, Braddom AE, Batugedara G, Bol S, Bunnik EM (2020) Naturally acquired humoral immunity against Plasmodium falciparum malaria. Front Immunol 11:594653. https://doi.org/10.3389/fimmu.2020.594653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Brody DL, Holtzman DM (2008) Active and passive immunotherapy for neurodegenerative disorders. Annu Rev Neurosci 31:175–193. https://doi.org/10.1146/annurev.neuro.31.060407.125529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Gustafsson G, Eriksson F, Moller C, da Fonseca TL, Outeiro TF, Lannfelt L, Bergstrom J, Ingelsson M (2017) Cellular uptake of alpha-synuclein oligomer-selective antibodies is enhanced by the extracellular presence of alpha-synuclein and mediated via Fcgamma receptors. Cell Mol Neurobiol 37(1):121–131. https://doi.org/10.1007/s10571-016-0352-5

    Article  CAS  PubMed  Google Scholar 

  145. Nordstrom E, Eriksson F, Sigvardson J, Johannesson M, Kasrayan A, Jones-Kostalla M, Appelkvist P, Soderberg L et al. (2021) ABBV-0805, a novel antibody selective for soluble aggregated alpha-synuclein, prolongs lifespan and prevents buildup of alpha-synuclein pathology in mouse models of Parkinson’s disease. Neurobiol Dis 161:105543. https://doi.org/10.1016/j.nbd.2021.105543

    Article  CAS  PubMed  Google Scholar 

  146. Huang YR, Xie XX, Ji M, Yu XL, Zhu J, Zhang LX, Liu XG, Wei C et al. (2019) Naturally occurring autoantibodies against alpha-synuclein rescues memory and motor deficits and attenuates alpha-synuclein pathology in mouse model of Parkinson’s disease. Neurobiol Dis 124:202–217. https://doi.org/10.1016/j.nbd.2018.11.024

    Article  CAS  PubMed  Google Scholar 

  147. Jankovic J, Goodman I, Safirstein B, Marmon TK, Schenk DB, Koller M, Zago W, Ness DK et al. (2018) Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-alpha-synuclein monoclonal antibody, in patients with Parkinson disease: a randomized clinical trial. JAMA Neurol 75(10):1206–1214. https://doi.org/10.1001/jamaneurol.2018.1487

    Article  PubMed  PubMed Central  Google Scholar 

  148. Kuchimanchi M, Monine M, Kandadi Muralidharan K, Woodward C, Penner N (2020) Phase II dose selection for alpha synuclein-targeting antibody cinpanemab (BIIB054) based on target protein binding levels in the brain. CPT Pharmacometrics Syst Pharmacol 9(9):515–522. https://doi.org/10.1002/psp4.12538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Brys M, Fanning L, Hung S, Ellenbogen A, Penner N, Yang M, Welch M, Koenig E et al. (2019) Randomized phase I clinical trial of anti-alpha-synuclein antibody BIIB054. Mov Disord 34(8):1154–1163. https://doi.org/10.1002/mds.27738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Valera E, Masliah E (2013) Immunotherapy for neurodegenerative diseases: focus on alpha-synucleinopathies. Pharmacol Ther 138(3):311–322. https://doi.org/10.1016/j.pharmthera.2013.01.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Mandler M, Valera E, Rockenstein E, Mante M, Weninger H, Patrick C, Adame A, Schmidhuber S et al. (2015) Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy. Mol Neurodegener 10:10. https://doi.org/10.1186/s13024-015-0008-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Mandler M, Valera E, Rockenstein E, Weninger H, Patrick C, Adame A, Santic R, Meindl S et al. (2014) Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials. Acta Neuropathol 127(6):861–879. https://doi.org/10.1007/s00401-014-1256-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Schofield DJ, Irving L, Calo L, Bogstedt A, Rees G, Nuccitelli A, Narwal R, Petrone M et al. (2019) Preclinical development of a high affinity alpha-synuclein antibody, MEDI1341, that can enter the brain, sequester extracellular alpha-synuclein and attenuate alpha-synuclein spreading in vivo. Neurobiol Dis 132:104582. https://doi.org/10.1016/j.nbd.2019.104582

    Article  CAS  PubMed  Google Scholar 

  154. Cheng L, Zhang J, Li XY, Yuan L, Pan YF, Chen XR, Gao TM, Qiao JT et al. (2017) A novel antibody targeting sequence 31–35 in amyloid beta protein attenuates Alzheimer’s disease-related neuronal damage. Hippocampus 27(2):122–133. https://doi.org/10.1002/hipo.22676

    Article  CAS  PubMed  Google Scholar 

  155. Abushouk AI, Elmaraezy A, Aglan A, Salama R, Fouda S, Fouda R, AlSafadi AM (2017) Bapineuzumab for mild to moderate Alzheimer’s disease: a meta-analysis of randomized controlled trials. BMC Neurol 17(1):66. https://doi.org/10.1186/s12883-017-0850-1

    Article  PubMed  PubMed Central  Google Scholar 

  156. Lu M, Brashear HR (2019) Pharmacokinetics, pharmacodynamics, and safety of subcutaneous bapineuzumab: a single-ascending-dose study in patients with mild to moderate Alzheimer disease. Clin Pharmacol Drug Dev 8(3):326–335. https://doi.org/10.1002/cpdd.584

    Article  CAS  PubMed  Google Scholar 

  157. Doggrell SA (2018) Grasping at straws: the failure of solanezumab to modify mild Alzheimer’s disease. Expert Opin Biol Ther 18(12):1189–1192. https://doi.org/10.1080/14712598.2018.1543397

    Article  CAS  PubMed  Google Scholar 

  158. Klein G, Delmar P, Voyle N, Rehal S, Hofmann C, Abi-Saab D, Andjelkovic M, Ristic S et al. (2019) Gantenerumab reduces amyloid-beta plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis. Alzheimers Res Ther 11(1):101. https://doi.org/10.1186/s13195-019-0559-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ostrowitzki S, Lasser RA, Dorflinger E, Scheltens P, Barkhof F, Nikolcheva T, Ashford E, Retout S et al. (2017) A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther 9(1):95. https://doi.org/10.1186/s13195-017-0318-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Ultsch M, Li B, Maurer T, Mathieu M, Adolfsson O, Muhs A, Pfeifer A, Pihlgren M et al. (2016) Structure of crenezumab complex with Abeta shows loss of beta-hairpin. Sci Rep 6:39374. https://doi.org/10.1038/srep39374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Yang T, Dang Y, Ostaszewski B, Mengel D, Steffen V, Rabe C, Bittner T, Walsh DM et al. (2019) Target engagement in an alzheimer trial: crenezumab lowers amyloid beta oligomers in cerebrospinal fluid. Ann Neurol 86(2):215–224. https://doi.org/10.1002/ana.25513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S et al. (2016) The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature 537(7618):50–56. https://doi.org/10.1038/nature19323

    Article  CAS  PubMed  Google Scholar 

  163. Arndt JW, Qian F, Smith BA, Quan C, Kilambi KP, Bush MW, Walz T, Pepinsky RB et al. (2018) Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-beta. Sci Rep 8(1):6412. https://doi.org/10.1038/s41598-018-24501-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Landen JW, Andreasen N, Cronenberger CL, Schwartz PF, Borjesson-Hanson A, Ostlund H, Sattler CA, Binneman B et al. (2017) Ponezumab in mild-to-moderate Alzheimer’s disease: randomized phase II PET-PIB study. Alzheimers Dement (N Y) 3(3):393–401. https://doi.org/10.1016/j.trci.2017.05.003

    Article  Google Scholar 

  165. Landen JW, Cohen S, Billing CB Jr, Cronenberger C, Styren S, Burstein AH, Sattler C, Lee JH et al. (2017) Multiple-dose ponezumab for mild-to-moderate Alzheimer’s disease: safety and efficacy. Alzheimers Dement (N Y) 3(3):339–347. https://doi.org/10.1016/j.trci.2017.04.003

    Article  Google Scholar 

  166. Bayer AJ, Bullock R, Jones RW, Wilkinson D, Paterson KR, Jenkins L, Millais SB, Donoghue S (2005) Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology 64(1):94–101. https://doi.org/10.1212/01.WNL.0000148604.77591.67

    Article  CAS  PubMed  Google Scholar 

  167. Vukicevic M, Fiorini E, Siegert S, Carpintero R, Rincon-Restrepo M, Lopez-Deber P, Piot N, Ayer M et al. (2022) An amyloid beta vaccine that safely drives immunity to a key pathological species in Alzheimer’s disease: pyroglutamate amyloid beta. Brain Commun 4(1):fcac022. https://doi.org/10.1093/braincomms/fcac022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Vandenberghe R, Riviere ME, Caputo A, Sovago J, Maguire RP, Farlow M, Marotta G, Sanchez-Valle R et al. (2017) Active Abeta immunotherapy CAD106 in Alzheimer’s disease: a phase 2b study. Alzheimers Dement (N Y) 3(1):10–22. https://doi.org/10.1016/j.trci.2016.12.003

    Article  Google Scholar 

  169. Winblad B, Andreasen N, Minthon L, Floesser A, Imbert G, Dumortier T, Maguire RP, Blennow K et al. (2012) Safety, tolerability, and antibody response of active Abeta immunotherapy with CAD106 in patients with Alzheimer’s disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol 11(7):597–604. https://doi.org/10.1016/S1474-4422(12)70140-0

    Article  CAS  PubMed  Google Scholar 

  170. Hull M, Sadowsky C, Arai H, Le Prince LG, Holstein A, Booth K, Peng Y, Yoshiyama T et al. (2017) Long-term extensions of randomized vaccination trials of ACC-001 and QS-21 in mild to moderate Alzheimer’s disease. Curr Alzheimer Res 14(7):696–708. https://doi.org/10.2174/1567205014666170117101537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Ketter N, Liu E, Di J, Honig LS, Lu M, Novak G, Werth J, LePrinceLeterme G et al. (2016) A randomized double-blind, phase 2 study of the effects of the vaccine Vanutide Cridificar with QS-21 adjuvant on immunogenicity safety and amyloid imaging in patients with mild to moderate Alzheimer’s disease. J Prev Alzheimers Dis 3(4):192–201. https://doi.org/10.14283/jpad.2016.118

    Article  CAS  PubMed  Google Scholar 

  172. Lacosta AM, Pascual-Lucas M, Pesini P, Casabona D, Perez-Grijalba V, Marcos-Campos I, Sarasa L, Canudas J et al. (2018) Safety, tolerability and immunogenicity of an active anti-Abeta40 vaccine (ABvac40) in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase I trial. Alzheimers Res Ther 10(1):12. https://doi.org/10.1186/s13195-018-0340-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Rajamohamedsait H, Rasool S, Rajamohamedsait W, Lin Y, Sigurdsson EM (2017) Prophylactic active tau immunization leads to sustained reduction in both tau and amyloid-beta pathologies in 3xTg mice. Sci Rep 7(1):17034. https://doi.org/10.1038/s41598-017-17313-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Kontsekova E, Zilka N, Kovacech B, Novak P, Novak M (2014) First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res Ther 6(4):44. https://doi.org/10.1186/alzrt278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Ayalon G, Lee SH, Adolfsson O, Foo-Atkins C, Atwal JK, Blendstrup M, Booler H, Bravo J et al. (2021) Antibody semorinemab reduces tau pathology in a transgenic mouse model and engages tau in patients with Alzheimer’s disease. Sci Transl Med 13 (593). https://doi.org/10.1126/scitranslmed.abb2639

  176. van Ameijde J, Crespo R, Janson R, Juraszek J, Siregar B, Verveen H, Sprengers I, Nahar T et al. (2018) Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser(422) containing epitope on pathological tau. Acta Neuropathol Commun 6(1):59. https://doi.org/10.1186/s40478-018-0562-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Dai CL, Hu W, Tung YC, Liu F, Gong CX, Iqbal K (2018) Tau passive immunization blocks seeding and spread of Alzheimer hyperphosphorylated Tau-induced pathology in 3 x Tg-AD mice. Alzheimers Res Ther 10(1):13. https://doi.org/10.1186/s13195-018-0341-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Castillo-Carranza DL, Sengupta U, Guerrero-Munoz MJ, Lasagna-Reeves CA, Gerson JE, Singh G, Estes DM, Barrett AD et al. (2014) Passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J Neurosci 34(12):4260–4272. https://doi.org/10.1523/JNEUROSCI.3192-13.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Breijyeh Z, Karaman R (2020) Comprehensive review on Alzheimer’s disease: causes and treatment. Molecules 25 (24). https://doi.org/10.3390/molecules25245789

  180. Rosenqvist N, Asuni AA, Andersson CR, Christensen S, Daechsel JA, Egebjerg J, Falsig J, Helboe L et al. (2018) Highly specific and selective anti-pS396-tau antibody C10.2 targets seeding-competent tau. Alzheimers Dement (N Y) 4:521–534. https://doi.org/10.1016/j.trci.2018.09.005

    Article  Google Scholar 

  181. West T, Hu Y, Verghese PB, Bateman RJ, Braunstein JB, Fogelman I, Budur K, Florian H et al. (2017) Preclinical and clinical development of ABBV-8E12, a humanized anti-tau antibody, for treatment of Alzheimer’s disease and other tauopathies. J Prev Alzheimers Dis 4(4):236–241. https://doi.org/10.14283/jpad.2017.36

    Article  CAS  PubMed  Google Scholar 

  182. Amaro IA, Henderson LA (2016) An intrabody drug (rAAV6-INT41) reduces the binding of N-terminal huntingtin fragment(s) to DNA to basal levels in PC12 cells and delays cognitive loss in the R6/2 animal model. J Neurodegener Dis 2016:7120753. https://doi.org/10.1155/2016/7120753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Lecerf JM, Shirley TL, Zhu Q, Kazantsev A, Amersdorfer P, Housman DE, Messer A, Huston JS (2001) Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington’s disease. Proc Natl Acad Sci U S A 98(8):4764–4769. https://doi.org/10.1073/pnas.071058398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Cattepoel S, Hanenberg M, Kulic L, Nitsch RM (2011) Chronic intranasal treatment with an anti-Abeta(30–42) scFv antibody ameliorates amyloid pathology in a transgenic mouse model of Alzheimer’s disease. PLoS ONE 6(4):e18296. https://doi.org/10.1371/journal.pone.0018296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Vitale F, Giliberto L, Ruiz S, Steslow K, Marambaud P, d’Abramo C (2018) Anti-tau conformational scFv MC1 antibody efficiently reduces pathological tau species in adult JNPL3 mice. Acta Neuropathol Commun 6(1):82. https://doi.org/10.1186/s40478-018-0585-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Khoshnan A, Ko J, Patterson PH (2002) Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity. Proc Natl Acad Sci U S A 99(2):1002–1007. https://doi.org/10.1073/pnas.022631799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Lorenzen N, Nielsen SB, Yoshimura Y, Vad BS, Andersen CB, Betzer C, Kaspersen JD, Christiansen G et al. (2014) How epigallocatechin gallate can inhibit alpha-synuclein oligomer toxicity in vitro. J Biol Chem 289(31):21299–21310. https://doi.org/10.1074/jbc.M114.554667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Zhao D, Xu YM, Cao LQ, Yu F, Zhou H, Qin W, Li HJ, He CX et al. (2021) Complex crystal structure determination and in vitro anti-non-small cell lung cancer activity of Hsp90 (N) inhibitor SNX-2112. Front Cell Dev Biol 9:650106. https://doi.org/10.3389/fcell.2021.650106

    Article  PubMed  PubMed Central  Google Scholar 

  189. Opattova A, Filipcik P, Cente M, Novak M (2013) Intracellular degradation of misfolded tau protein induced by geldanamycin is associated with activation of proteasome. J Alzheimers Dis 33(2):339–348. https://doi.org/10.3233/JAD-2012-121072

    Article  CAS  PubMed  Google Scholar 

  190. Zare N, Motamedi F, Digaleh H, Khodagholi F, Maghsoudi N (2015) Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning. Cell Stress Chaperones 20(2):309–319. https://doi.org/10.1007/s12192-014-0550-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Sittler A, Lurz R, Lueder G, Priller J, Lehrach H, Hayer-Hartl MK, Hartl FU, Wanker EE (2001) Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington’s disease. Hum Mol Genet 10(12):1307–1315. https://doi.org/10.1093/hmg/10.12.1307

    Article  CAS  PubMed  Google Scholar 

  192. Chen Y, Wang B, Liu D, Li JJ, Xue Y, Sakata K, Zhu LQ, Heldt SA et al. (2014) Hsp90 chaperone inhibitor 17-AAG attenuates Abeta-induced synaptic toxicity and memory impairment. J Neurosci 34(7):2464–2470. https://doi.org/10.1523/JNEUROSCI.0151-13.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Sharma S, Sharma N, Saini A, Nehru B (2019) Carbenoxolone reverses the amyloid beta 1–42 oligomer-induced oxidative damage and anxiety-related behavior in rats. Neurotox Res 35(3):654–667. https://doi.org/10.1007/s12640-018-9975-2

    Article  CAS  PubMed  Google Scholar 

  194. Cao F, Wang Y, Peng B, Zhang X, Zhang D, Xu L (2018) Effects of celastrol on Tau hyperphosphorylation and expression of HSF-1 and HSP70 in SH-SY5Y neuroblastoma cells induced by amyloid-beta peptides. Biotechnol Appl Biochem 65(3):390–396. https://doi.org/10.1002/bab.1633

    Article  CAS  PubMed  Google Scholar 

  195. Paris D, Ganey NJ, Laporte V, Patel NS, Beaulieu-Abdelahad D, Bachmeier C, March A, Ait-Ghezala G et al. (2010) Reduction of beta-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer’s disease. J Neuroinflammation 7:17. https://doi.org/10.1186/1742-2094-7-17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Wang J, Gines S, MacDonald ME, Gusella JF (2005) Reversal of a full-length mutant huntingtin neuronal cell phenotype by chemical inhibitors of polyglutamine-mediated aggregation. BMC Neurosci 6:1. https://doi.org/10.1186/1471-2202-6-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, Kurosawa M, Nekooki M et al. (2004) Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 10(2):148–154. https://doi.org/10.1038/nm985

    Article  CAS  PubMed  Google Scholar 

  198. Shaltiel-Karyo R, Frenkel-Pinter M, Rockenstein E, Patrick C, Levy-Sakin M, Schiller A, Egoz-Matia N, Masliah E et al. (2013) A blood-brain barrier (BBB) disrupter is also a potent alpha-synuclein (alpha-syn) aggregation inhibitor: a novel dual mechanism of mannitol for the treatment of Parkinson disease (PD). J Biol Chem 288(24):17579–17588. https://doi.org/10.1074/jbc.M112.434787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Huang F, Wang J, Qu A, Shen L, Liu J, Liu J, Zhang Z, An Y et al. (2014) Maintenance of amyloid beta peptide homeostasis by artificial chaperones based on mixed-shell polymeric micelles. Angew Chem Int Ed Engl 53(34):8985–8990. https://doi.org/10.1002/anie.201400735

    Article  CAS  PubMed  Google Scholar 

  200. Singh MP, Mishra M, Sharma A, Shukla AK, Mudiam MK, Patel DK, Ram KR, Chowdhuri DK (2011) Genotoxicity and apoptosis in Drosophila melanogaster exposed to benzene, toluene and xylene: attenuation by quercetin and curcumin. Toxicol Appl Pharmacol 253(1):14–30. https://doi.org/10.1016/j.taap.2011.03.006

    Article  CAS  PubMed  Google Scholar 

  201. Choi JH, Choi AY, Yoon H, Choe W, Yoon KS, Ha J, Yeo EJ, Kang I (2010) Baicalein protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis through inhibition of reactive oxygen species production and CHOP induction. Exp Mol Med 42(12):811–822. https://doi.org/10.3858/emm.2010.42.12.084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Tatenhorst L, Eckermann K, Dambeck V, Fonseca-Ornelas L, Walle H, Lopes da Fonseca T, Koch JC, Becker S et al. (2016) Fasudil attenuates aggregation of alpha-synuclein in models of Parkinson’s disease. Acta Neuropathol Commun 4:39. https://doi.org/10.1186/s40478-016-0310-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Limbocker R, Staats R, Chia S, Ruggeri FS, Mannini B, Xu CK, Perni M, Cascella R et al. (2021) Squalamine and its derivatives modulate the aggregation of amyloid-beta and alpha-synuclein and suppress the toxicity of their oligomers. Front Neurosci 15:680026. https://doi.org/10.3389/fnins.2021.680026

    Article  PubMed  PubMed Central  Google Scholar 

  204. Perni M, Flagmeier P, Limbocker R, Cascella R, Aprile FA, Galvagnion C, Heller GT, Meisl G et al. (2018) Multistep inhibition of alpha-synuclein aggregation and toxicity in vitro and in vivo by trodusquemine. ACS Chem Biol 13(8):2308–2319. https://doi.org/10.1021/acschembio.8b00466

    Article  CAS  PubMed  Google Scholar 

  205. Schwab K, Frahm S, Horsley D, Rickard JE, Melis V, Goatman EA, Magbagbeolu M, Douglas M et al. (2017) A protein aggregation inhibitor, leuco-methylthioninium bis(hydromethanesulfonate), decreases alpha-synuclein inclusions in a transgenic mouse model of synucleinopathy. Front Mol Neurosci 10:447. https://doi.org/10.3389/fnmol.2017.00447

    Article  CAS  PubMed  Google Scholar 

  206. Attar A, Chan WT, Klarner FG, Schrader T, Bitan G (2014) Safety and pharmacological characterization of the molecular tweezer CLR01 - a broad-spectrum inhibitor of amyloid proteins’ toxicity. BMC Pharmacol Toxicol 15:23. https://doi.org/10.1186/2050-6511-15-23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Deeg AA, Reiner AM, Schmidt F, Schueder F, Ryazanov S, Ruf VC, Giller K, Becker S et al. (1850) Zinth W (2015) Anle138b and related compounds are aggregation specific fluorescence markers and reveal high affinity binding to alpha-synuclein aggregates. Biochim Biophys Acta 9:1884–1890. https://doi.org/10.1016/j.bbagen.2015.05.021

    Article  CAS  Google Scholar 

  208. Mahia A, Pena-Diaz S, Navarro S, Jose Galano-Frutos J, Pallares I, Pujols J, Diaz-de-Villegas MD, Galvez JA et al. (2021) Design, synthesis and structure-activity evaluation of novel 2-pyridone-based inhibitors of alpha-synuclein aggregation with potentially improved BBB permeability. Bioorg Chem 117:105472. https://doi.org/10.1016/j.bioorg.2021.105472

    Article  CAS  PubMed  Google Scholar 

  209. Castro-Caldas M, Carvalho AN, Rodrigues E, Henderson CJ, Wolf CR, Rodrigues CM, Gama MJ (2012) Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson’s disease. Mol Neurobiol 46(2):475–486. https://doi.org/10.1007/s12035-012-8295-4

    Article  CAS  PubMed  Google Scholar 

  210. Nunes AF, Amaral JD, Lo AC, Fonseca MB, Viana RJ, Callaerts-Vegh Z, D’Hooge R, Rodrigues CM (2012) TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid-beta deposition in APP/PS1 mice. Mol Neurobiol 45(3):440–454. https://doi.org/10.1007/s12035-012-8256-y

    Article  CAS  PubMed  Google Scholar 

  211. Qi H, Shen D, Jiang C, Wang H, Chang M (2021) Ursodeoxycholic acid protects dopaminergic neurons from oxidative stress via regulating mitochondrial function, autophagy, and apoptosis in MPTP/MPP(+)-induced Parkinson’s disease. Neurosci Lett 741:135493. https://doi.org/10.1016/j.neulet.2020.135493

    Article  CAS  PubMed  Google Scholar 

  212. Batarseh YS, Mohamed LA, Al Rihani SB, Mousa YM, Siddique AB, El Sayed KA, Kaddoumi A (2017) Oleocanthal ameliorates amyloid-beta oligomers’ toxicity on astrocytes and neuronal cells: in vitro studies. Neuroscience 352:204–215. https://doi.org/10.1016/j.neuroscience.2017.03.059

    Article  CAS  PubMed  Google Scholar 

  213. Schneider SA, Alcalay RN (2020) Precision medicine for Parkinson’s disease: Ambroxol for glucocerebrosidase-associated Parkinson’s disease, first trial completed. Mov Disord 35(7):1134–1135. https://doi.org/10.1002/mds.28072

    Article  PubMed  Google Scholar 

  214. Friesen EL, De Snoo ML, Rajendran L, Kalia LV, Kalia SK (2017) Chaperone-based therapies for disease modification in Parkinson’s disease. Parkinsons Dis 2017:5015307. https://doi.org/10.1155/2017/5015307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Vidoni C, Secomandi E, Castiglioni A, Melone MAB, Isidoro C (2018) Resveratrol protects neuronal-like cells expressing mutant huntingtin from dopamine toxicity by rescuing ATG4-mediated autophagosome formation. Neurochem Int 117:174–187. https://doi.org/10.1016/j.neuint.2017.05.013

    Article  CAS  PubMed  Google Scholar 

  216. Choi JG, Kim N, Huh E, Lee H, Oh MH, Park JD, Pyo MK, Oh MS (2017) White ginseng protects mouse hippocampal cells against amyloid-beta oligomer toxicity. Phytother Res 31(3):497–506. https://doi.org/10.1002/ptr.5776

    Article  CAS  PubMed  Google Scholar 

  217. Bukhari SN, Jantan I, Masand VH, Mahajan DT, Sher M, Naeem-ul-Hassan M, Amjad MW (2014) Synthesis of alpha, beta-unsaturated carbonyl based compounds as acetylcholinesterase and butyrylcholinesterase inhibitors: characterization, molecular modeling, QSAR studies and effect against amyloid beta-induced cytotoxicity. Eur J Med Chem 83:355–365. https://doi.org/10.1016/j.ejmech.2014.06.034

    Article  CAS  PubMed  Google Scholar 

  218. Nguyen P, Oumata N, Soubigou F, Evrard J, Desban N, Lemoine P, Bouaziz S, Blondel M et al. (2014) Evaluation of the antiprion activity of 6-aminophenanthridines and related heterocycles. Eur J Med Chem 82:363–371. https://doi.org/10.1016/j.ejmech.2014.05.083

    Article  CAS  PubMed  Google Scholar 

  219. Guzior N, Bajda M, Skrok M, Kurpiewska K, Lewinski K, Brus B, Pislar A, Kos J et al. (2015) Development of multifunctional, heterodimeric isoindoline-1,3-dione derivatives as cholinesterase and beta-amyloid aggregation inhibitors with neuroprotective properties. Eur J Med Chem 92:738–749. https://doi.org/10.1016/j.ejmech.2015.01.027

    Article  CAS  PubMed  Google Scholar 

  220. Ahmad S, Jo MH, Ikram M, Khan A, Kim MO (2021) Deciphering the potential neuroprotective effects of luteolin against Abeta1–42-induced Alzheimer’s disease. Int J Mol Sci 22 (17). https://doi.org/10.3390/ijms22179583

  221. Oliveira AM, Cardoso SM, Ribeiro M, Seixas RS, Silva AM, Rego AC (2015) Protective effects of 3-alkyl luteolin derivatives are mediated by Nrf2 transcriptional activity and decreased oxidative stress in Huntington’s disease mouse striatal cells. Neurochem Int 91:1–12. https://doi.org/10.1016/j.neuint.2015.10.004

    Article  CAS  PubMed  Google Scholar 

  222. Zhou Y, Vu K, Chen Y, Pham J, Brady T, Liu G, Chen J, Nam J et al. (2009) Chloro-oxime derivatives as novel small molecule chaperone amplifiers. Bioorg Med Chem Lett 19(11):3128–3135. https://doi.org/10.1016/j.bmcl.2009.03.011

    Article  CAS  PubMed  Google Scholar 

  223. Okamoto M, Gray JD, Larson CS, Kazim SF, Soya H, McEwen BS, Pereira AC (2018) Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer’s disease. Transl Psychiatry 8(1):153. https://doi.org/10.1038/s41398-018-0201-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Schiefer J, Landwehrmeyer GB, Luesse HG, Sprunken A, Puls C, Milkereit A, Milkereit E, Kosinski CM (2002) Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington’s disease. Mov Disord 17(4):748–757. https://doi.org/10.1002/mds.10229

    Article  PubMed  Google Scholar 

  225. Zhang B, Au Q, Yoon IS, Tremblay MH, Yip G, Zhou Y, Barber JR, Ng SC (2009) Identification of small-molecule HSF1 amplifiers by high content screening in protection of cells from stress induced injury. Biochem Biophys Res Commun 390(3):925–930. https://doi.org/10.1016/j.bbrc.2009.10.079

    Article  CAS  PubMed  Google Scholar 

  226. Wang B, Liu Y, Huang L, Chen J, Li JJ, Wang R, Kim E, Chen Y et al. (2017) A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer’s mouse model via an HSF1-mediated mechanism. Mol Psychiatry 22(7):990–1001. https://doi.org/10.1038/mp.2016.104

    Article  CAS  PubMed  Google Scholar 

  227. Smith AV, Tabrizi SJ (2020) Therapeutic antisense targeting of huntingtin. DNA Cell Biol 39(2):154–158. https://doi.org/10.1089/dna.2019.5188

    Article  CAS  PubMed  Google Scholar 

  228. Uehara T, Choong CJ, Nakamori M, Hayakawa H, Nishiyama K, Kasahara Y, Baba K, Nagata T et al. (2019) Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting alpha-synuclein as a novel therapy for Parkinson’s disease. Sci Rep 9(1):7567. https://doi.org/10.1038/s41598-019-43772-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Zhao HT, John N, Delic V, Ikeda-Lee K, Kim A, Weihofen A, Swayze EE, Kordasiewicz HB et al. (2017) LRRK2 antisense oligonucleotides ameliorate alpha-synuclein inclusion formation in a Parkinson’s disease mouse model. Mol Ther Nucleic Acids 8:508–519. https://doi.org/10.1016/j.omtn.2017.08.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Chang JL, Hinrich AJ, Roman B, Norrbom M, Rigo F, Marr RA, Norstrom EM, Hastings ML (2018) Targeting amyloid-beta precursor protein, APP, splicing with antisense oligonucleotides reduces toxic amyloid-beta production. Mol Ther 26(6):1539–1551. https://doi.org/10.1016/j.ymthe.2018.02.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Lu M, Liu T, Jiao Q, Ji J, Tao M, Liu Y, You Q, Jiang Z (2018) Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway. Eur J Med Chem 146:251–259. https://doi.org/10.1016/j.ejmech.2018.01.063

    Article  CAS  PubMed  Google Scholar 

  232. Chu Y, Muller S, Tavares A, Barret O, Alagille D, Seibyl J, Tamagnan G, Marek K et al. (2019) Intrastriatal alpha-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes. Brain 142(11):3565–3579. https://doi.org/10.1093/brain/awz296

    Article  PubMed  PubMed Central  Google Scholar 

  233. Silva MC, Ferguson FM, Cai Q, Donovan KA, Nandi G, Patnaik D, Zhang T, Huang HT et al. (2019) Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models. Elife 8. https://doi.org/10.7554/eLife.45457

  234. Arancibia S, Silhol M, Mouliere F, Meffre J, Hollinger I, Maurice T, Tapia-Arancibia L (2008) Protective effect of BDNF against beta-amyloid induced neurotoxicity in vitro and in vivo in rats. Neurobiol Dis 31(3):316–326. https://doi.org/10.1016/j.nbd.2008.05.012

    Article  CAS  PubMed  Google Scholar 

  235. Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, Wang L, Blesch A et al. (2009) Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med 15(3):331–337. https://doi.org/10.1038/nm.1912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Irwin DJ, Lee VM, Trojanowski JQ (2013) Parkinson’s disease dementia: convergence of alpha-synuclein, tau and amyloid-beta pathologies. Nat Rev Neurosci 14(9):626–636. https://doi.org/10.1038/nrn3549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Yang S, Chang R, Yang H, Zhao T, Hong Y, Kong HE, Sun X, Qin Z et al. (2017) CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease. J Clin Invest 127(7):2719–2724. https://doi.org/10.1172/JCI92087

    Article  PubMed  PubMed Central  Google Scholar 

  238. Gyorgy B, Loov C, Zaborowski MP, Takeda S, Kleinstiver BP, Commins C, Kastanenka K, Mu D et al. (2018) CRISPR/Cas9 mediated disruption of the Swedish APP allele as a therapeutic approach for early-onset Alzheimer’s disease. Mol Ther Nucleic Acids 11:429–440. https://doi.org/10.1016/j.omtn.2018.03.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Taguchi YV, Gorenberg EL, Nagy M, Thrasher D, Fenton WA, Volpicelli-Daley L, Horwich AL, Chandra SS (2019) Hsp110 mitigates alpha-synuclein pathology in vivo. Proc Natl Acad Sci U S A 116(48):24310–24316. https://doi.org/10.1073/pnas.1903268116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Singh MP, Ram KR, Mishra M, Shrivastava M, Saxena DK, Chowdhuri DK (2010) Effects of co-exposure of benzene, toluene and xylene to Drosophila melanogaster: alteration in hsp70, hsp60, hsp83, hsp26, ROS generation and oxidative stress markers. Chemosphere 79(5):577–587. https://doi.org/10.1016/j.chemosphere.2010.01.054

    Article  CAS  PubMed  Google Scholar 

  241. Singh MP, Reddy MM, Mathur N, Saxena DK, Chowdhuri DK (2009) Induction of hsp70, hsp60, hsp83 and hsp26 and oxidative stress markers in benzene, toluene and xylene exposed Drosophila melanogaster: role of ROS generation. Toxicol Appl Pharmacol 235(2):226–243. https://doi.org/10.1016/j.taap.2008.12.002

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are grateful to Lovely Professional University for providing infrastructure and library facilities.

Author information

Authors and Affiliations

  1. School of Bioengineering and Biosciences, Lovely Professional University, Delhi-Jalandhar GT Road, Phagwara, 144411, Punjab, India

    Gouri Chopra, Shabnam Shabir, Sumaira Yousuf, Simran Kauts, Ashiq H. Mir & Mahendra P. Singh

  2. Department of Zoology, Aligarh Muslim University, Aligarh, India

    Shahnawaz A. Bhat

Authors
  1. Gouri Chopra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shabnam Shabir
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sumaira Yousuf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simran Kauts
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shahnawaz A. Bhat
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ashiq H. Mir
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mahendra P. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, GC, and MPS; writing—original draft preparation, GC, SS, SY, S, AHM, MPS; writing—review and editing, MPS, SAB. “All authors have read and agreed to the published version of the manuscript.”

Corresponding authors

Correspondence to Shahnawaz A. Bhat or Mahendra P. Singh.

Ethics declarations

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chopra, G., Shabir, S., Yousuf, S. et al. Proteinopathies: Deciphering Physiology and Mechanisms to Develop Effective Therapies for Neurodegenerative Diseases. Mol Neurobiol 59, 7513–7540 (2022). https://doi.org/10.1007/s12035-022-03042-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-022-03042-8

Keywords

Search

Navigation