Abstract
Aggregation of particular proteins in the form of inclusion bodies or plaques followed by neuronal death is a hallmark of neurodegenerative proteopathies such as primary Parkinsonism, Alzheimer’s disease, Lou Gehrig’s disease, and Huntington’s chorea. Complex polygenic and environmental factors implicated in these proteopathies. Accumulation of proteins in these disorders indicates a substantial disruption in protein homeostasis (proteostasis). Proteostasis or cellular proteome homeostasis is attained by the synchronization of a group of cellular mechanisms called the proteostasis network (PN), which is responsible for the stability of the proteome and achieves the equilibrium between synthesis, folding, and degradation of proteins. In this review, we will discuss the different types of PN and the impact of PN component dysfunction on the four major neurodegenerative diseases mentioned earlier.
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Aalto UL, Roitto HM, Finne-Soveri H et al (2018) Use of anticholinergic drugs and its relationship with psychological well-being and mortality in long-term care facilities in Helsinki. J Am Med Dir Assoc 19:511–515. https://doi.org/10.1016/j.jamda.2017.11.013
Abeliovich A, Gitler AD (2016) Defects in trafficking bridge Parkinson’s disease pathology and genetics. Nature 539:207–216. https://doi.org/10.1038/nature20414
Abeywardana T, Pratt MR (2015) Extent of inhibition of alpha-synuclein aggregation in vitro by SUMOylation is conjugation site- and SUMO isoform-selective. Biochemistry 54:959–961. https://doi.org/10.1021/bi501512m
Abounit K, Scarabelli TM, Mccauley RB (2012) World J Biol Chem 3. https://doi.org/10.4331/wjbc.v3.i1.TOPIC
Al-Ramahi I, Giridharan SSP, Chen Y-C et al (2017a) Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein. eLife 6. https://doi.org/10.7554/eLife.29123
Al-Ramahi I, Giridharan SSP, Chen Y-C et al (2017b) Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein. eLife 6. https://doi.org/10.7554/eLife.29123
Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB Bioavailability of curcumin: problems and promises. Mol Pharm 4:807–818. https://doi.org/10.1021/mp700113r
Anderson DB, Zanella CA, Henley JM, Cimarosti H (2017) Sumoylation: implications for neurodegenerative diseases. Adv Exp Med Biol 963:261–281. https://doi.org/10.1007/978-3-319-50044-7_16
Anderson JP, Walker DE, Goldstein JM et al (2006) Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281:29739–29752. https://doi.org/10.1074/jbc.M600933200
Arai T, Hasegawa M, Akiyama H 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 351:602–611. https://doi.org/10.1016/j.bbrc.2006.10.093
Arakawa A, Handa N, Ohsawa N et al (2010) The C-terminal BAG domain of BAG5 induces conformational changes of the Hsp70 nucleotide-binding domain for ADP-ATP exchange. Structure (London, England : 1993) 18:309–319. https://doi.org/10.1016/j.str.2010.01.004
Ardito F, Giuliani M, Perrone D et al (2017) The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review). Int J Mol Med 40:271–280. https://doi.org/10.3892/ijmm.2017.3036
Arif M, Kazim SF, Grundke-Iqbal I et al (2014) Tau pathology involves protein phosphatase 2A in Parkinsonism-dementia of Guam. Proc Natl Acad Sci U S A 111:1144–1149. https://doi.org/10.1073/pnas.1322614111
Arotcarena M-L, Teil M, Dehay B (2019) Autophagy in synucleinopathy: the overwhelmed and defective machinery. Cells 8. https://doi.org/10.3390/cells8060565
Arrasate M, Finkbeiner S (2012) Protein aggregates in Huntington’s disease. Exp Neurol 238:1–11. https://doi.org/10.1016/j.expneurol.2011.12.013
Ashkenazi A, Bento CF, Ricketts T et al (2017a) Polyglutamine tracts regulate autophagy. Autophagy 13:1613–1614. https://doi.org/10.1080/15548627.2017.1336278
Ashkenazi A, Bento CF, Ricketts T et al (2017b) Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature 545:108–111. https://doi.org/10.1038/nature22078
Atkin G, Paulson H (2014) Ubiquitin pathways in neurodegenerative disease. Front Mol Neurosci 7:63. https://doi.org/10.3389/fnmol.2014.00063
Aufschnaiter A, Kohler V, Büttner S (2017) Taking out the garbage: cathepsin D and calcineurin in neurodegeneration. Neural Regen Res 12:1776–1779. https://doi.org/10.4103/1673-5374.219031
Auluck PK, Chan HYE, Trojanowski JQ et al (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science (New York, NY) 295:865–868. https://doi.org/10.1126/science.1067389
Avrahami L, Farfara D, Shaham-Kol M et al (2013) Inhibition of glycogen synthase kinase-3 ameliorates beta-amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the Alzheimer disease mouse model: in vivo and in vitro studies. J Biol Chem 288:1295–1306. https://doi.org/10.1074/jbc.M112.409250
Balestrino R, Schapira AHV (2018) Glucocerebrosidase and Parkinson disease: molecular, clinical, and therapeutic implications. Neuroscientist 24:540–559. https://doi.org/10.1177/1073858417748875
Bang J, Salvatore Spina BLM (2015) Frontotemporal dementia. Lancet 386. https://doi.org/10.1201/9781315381572
Bano D, Zanetti F, Mende Y, Nicotera P (2011) Neurodegenerative processes in Huntington’s disease. Cell Death Dis 2:e228. https://doi.org/10.1038/cddis.2011.112
Barker WW, Luis CA, Kashuba A, et al (2002) Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Disease and Associated Disorders 16:203–212. https://doi.org/10.1097/00002093-200210000-00001.
Barmada SJ, Skibinski G, Korb E et al (2010) Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis. J Neurosci 30:639–649. https://doi.org/10.1523/JNEUROSCI.4988-09.2010
Benbrook DM, Long A (2012) Integration of autophagy, proteasomal degradation, unfolded protein response and apoptosis. Exp Oncol 34:286–297
Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292:1552–1555. https://doi.org/10.1126/science.292.5521.1552
Bonafede R, Mariotti R (2017) ALS pathogenesis and therapeutic approaches: the role of mesenchymal stem cells and extracellular vesicles. Front Cell Neurosci 11:80. https://doi.org/10.3389/fncel.2017.00080
Boston-Howes W, Gibb SL, Williams EO et al (2006) Caspase-3 cleaves and inactivates the glutamate transporter EAAT2. J Biol Chem 281:14076–14084. https://doi.org/10.1074/jbc.M600653200
Buchan JR, Kolaitis R-M, Taylor JP, Parker R (2013) Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell 153:1461–1474
Bussiere R, Lacampagne A, Reiken S et al (2017) Amyloid β production is regulated by β2-adrenergic signaling-mediated post-translational modifications of the ryanodine receptor. J Biol Chem 292:10153–10168. https://doi.org/10.1074/jbc.M116.743070
Buxbaum JD, Thinakaran G, Koliatsos V et al (1998) Alzheimer amyloid protein precursor in the rat hippocampus: transport and processing through the perforant path. J Neurosci 18:9629–9637
Caccamo A, Majumder S, Richardson A et al (2010) Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-β, and tau: effects on cognitive impairments. J Biol Chem 285:13107–13120. https://doi.org/10.1074/jbc.M110.100420
Castegna A, Aksenov M, Aksenova M, et al (2002) Proteomic identification of oxidatively modified proteins in Alzheimer’s disease brain. Part I: creatine kinase BB, glutamine synthase, and ubiquitin carboxy-terminal hydrolase L-1. Free radical biology & medicine 33:562–571. https://doi.org/10.1016/s0891-5849(02)00914-0
Chakraborty J, Basso V, Ziviani E (2017) Post translational modification of Parkin. Biology Direct 12:1–11. https://doi.org/10.1186/s13062-017-0176-3.
Chan SF, Sucher NJ (2001) An NMDA receptor signaling complex with protein phosphatase 2A. J Neurosci 21:7985–7992
Chang C-C, Lin T-C, Ho H-L et al (2018) GLP-1 analogue liraglutide attenuates mutant huntingtin-induced neurotoxicity by restoration of neuronal insulin signaling. Int J Mol Sci 19. https://doi.org/10.3390/ijms19092505
Chang J, Lee S, Blackstone C (2014) Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation. J Clin Invest 124:5249–5262
Chang MC, Srinivasan K, Friedman BA et al (2017) Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation. J Exp Med 214:2611–2628
Chao T-K, Hu J, Pringsheim T (2017) Risk factors for the onset and progression of Huntington disease. Neurotoxicology 61:79–99. https://doi.org/10.1016/j.neuro.2017.01.005
Checler F, Alves da Costa C, Ancolio K et al (2000) Role of the proteasome in Alzheimer’s disease. Biochim Biophys Acta (BBA) - Mol Basis Dis 1502:133–138. https://doi.org/10.1016/S0925-4439(00)00039-9
Chen Y, Bodles AM, McPhie DL et al (2007) APP-BP1 inhibits Aβ42 levels by interacting with Presenilin-1. Mol Neurodegener 2:3. https://doi.org/10.1186/1750-1326-2-3
Chen Y-F, Chang Y-Y, Lan M-Y, et al (2017) Identification of VPS35 p.D620N mutation-related Parkinson’s disease in a Taiwanese family with successful bilateral subthalamic nucleus deep brain stimulation: a case report and literature review. BMC neurology 17:191. https://doi.org/10.1186/s12883-017-0972-5.
Chiasserini D, Paciotti S, Eusebi P et al (2015) Selective loss of glucocerebrosidase activity in sporadic Parkinson’s disease and dementia with Lewy bodies. Mol Neurodegener 10:15. https://doi.org/10.1186/s13024-015-0010-2
Cho J-H, Johnson GVW (2003) Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3β (GSK3β) plays a critical role in regulating tau’s ability to bind and stabilize microtubules. J Neurochem 88:349–358. https://doi.org/10.1111/j.1471-4159.2004.02155.x
Chopra V, Quinti L, Kim J et al (2012) The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington’s disease mouse models. Cell Rep 2:1492–1497. https://doi.org/10.1016/j.celrep.2012.11.001
Chung J-Y, Park HR, Lee S-J et al (2013) Elevated TRAF2/6 expression in Parkinson’s disease is caused by the loss of Parkin E3 ligase activity. Lab Investig 93:663–676. https://doi.org/10.1038/labinvest.2013.60
Cirulli ET, Lasseigne BN, Petrovski S et al (2015) Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347:1436–1441
Cleveland DW, Rothstein JD (2001) From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci 2:806
Contestabile A (2011) Amyotrophic lateral sclerosis: from research to therapeutic attempts and therapeutic perspectives. Curr Med Chem 18:5655–5665
Coppede F, Migliore L (2015) DNA damage in neurodegenerative diseases. Mutat Res 776:84–97. https://doi.org/10.1016/j.mrfmmm.2014.11.010
Cuervo AM, Wong E (2014) Chaperone-mediated autophagy: roles in disease and aging. Cell Res 24:92–104. https://doi.org/10.1038/cr.2013.153
Damiano M, Galvan L, Déglon N, Brouillet E (2010) Mitochondria in Huntington’s disease. Biochim Biophys Acta 1802:52–61. https://doi.org/10.1016/j.bbadis.2009.07.012
Davenport J, Manjarrez JR, Peterson L et al (2011) Gambogic acid, a natural product inhibitor of Hsp90. J Nat Prod 74:1085–1092. https://doi.org/10.1021/np200029q
Davies SW, Turmaine M, Cozens BA et al (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90:537–548. https://doi.org/10.1016/S0092-8674(00)80513-9
Dehay B, Bove J, Rodriguez-Muela N et al (2010) Pathogenic lysosomal depletion in Parkinson’s disease. J Neurosci 30:12535–12544. https://doi.org/10.1523/JNEUROSCI.1920-10.2010
Dehay B, Ramirez A, Martinez-Vicente M et al (2012) Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration. Proc Natl Acad Sci U S A 109:9611–9616. https://doi.org/10.1073/pnas.1112368109
DeJesus-Hernandez M, Mackenzie IR, Boeve BF et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256
Del Prete D, Checler F, Chami M (2014) Ryanodine receptors: physiological function and deregulation in Alzheimer disease. Mol Neurodegener 9:21. https://doi.org/10.1186/1750-1326-9-21
Dickey C, Kraft C, Jinwal U et al (2009) Aging analysis reveals slowed Tau turnover and enhanced stress response in a mouse model of tauopathy. Am J Pathol 174:228–238. https://doi.org/10.2353/ajpath.2009.080764
DiFiglia M, Sapp E, Chase KO et al (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science (New York, NY) 277:1990–1993. https://doi.org/10.1126/science.277.5334.1990
Doble BW, Woodgett JR (2007) Role of glycogen synthase kinase-3 in cell fate and epithelial-mesenchymal transitions. Cells Tissues Organs 185:73–84. https://doi.org/10.1159/000101306
Dos Santos Picanco LC, Ozela PF, de Fatima de Brito Brito M et al (2018) Alzheimer’s disease: a review from the pathophysiology to diagnosis, new perspectives for pharmacological treatment. Curr Med Chem 25:3141–3159. https://doi.org/10.2174/0929867323666161213101126
Dou F, Netzer WJ, Tanemura K et al (2003) Chaperones increase association of tau protein with microtubules. Proc Natl Acad Sci 100:721–726. https://doi.org/10.1073/pnas.242720499
Dreser A, Vollrath JT, Sechi A et al (2017) The ALS-linked E102Q mutation in Sigma receptor-1 leads to ER stress-mediated defects in protein homeostasis and dysregulation of RNA-binding proteins. Cell Death Differ 24:1655
Eckman EA, Reed DK, Eckman CB (2001) Degradation of the Alzheimer’s amyloid β peptide by endothelin-converting enzyme. J Biol Chem 276:24540–24548. https://doi.org/10.1074/jbc.M007579200
Farah CA, Nguyen MD, Julien JP, Leclerc N (2003) Altered levels and distribution of microtubule-associated proteins before disease onset in a mouse model of amyotrophic lateral sclerosis. J Neurochem 84:77–86. https://doi.org/10.1046/j.1471-4159.2003.01505.x
Faust K, Gehrke S, Yang Y et al (2009) Neuroprotective effects of compounds with antioxidant and anti-inflammatory properties in a Drosophila model of Parkinson’s disease. BMC Neurosci 10:109. https://doi.org/10.1186/1471-2202-10-109
Fei E, Jia N, Yan M et al (2006) SUMO-1 modification increases human SOD1 stability and aggregation. Biochem Biophys Res Commun 347:406–412. https://doi.org/10.1016/j.bbrc.2006.06.092
Feng H-L, Leng Y, Ma C-H et al (2008) Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience 155:567–572. https://doi.org/10.1016/j.neuroscience.2008.06.040
Flower TR, Chesnokova LS, Froelich CA et al (2005) Heat shock prevents alpha-synuclein-induced apoptosis in a yeast model of Parkinson’s disease. J Mol Biol 351:1081–1100. https://doi.org/10.1016/j.jmb.2005.06.060
Foran E, Bogush A, Goffredo M et al (2011) Motor neuron impairment mediated by a sumoylated fragment of the glial glutamate transporter EAAT2. Glia 59:1719–1731. https://doi.org/10.1002/glia.21218
Foran E, Rosenblum L, Bogush AI, Trotti D (2013) Sumoylation of critical proteins in amyotrophic lateral sclerosis: emerging pathways of pathogenesis. NeuroMolecular Med 15:760–770. https://doi.org/10.1007/s12017-013-8262-x
Forde JE, Dale TC (2007) Glycogen synthase kinase 3: a key regulator of cellular fate. Cell Mol Life Sci 64:1930–1944. https://doi.org/10.1007/s00018-007-7045-7
Fornai F, Longone P, Cafaro L et al (2008) Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 105:2052–2057. https://doi.org/10.1073/pnas.0708022105
Friesen EL, De Snoo ML, Rajendran L et al (2017) Chaperone-based therapies for disease modification in Parkinson’s disease. Parkinson’s Dis 2017:5015307. https://doi.org/10.1155/2017/5015307
Gadhave K, Bolshette N, Ahire A et al (2016) The ubiquitin proteasomal system: a potential target for the management of Alzheimer’s disease. J Cell Mol Med 20:1392–1407. https://doi.org/10.1111/jcmm.12817
Gal J, Chen J, Barnett KR et al (2013) HDAC6 regulates mutant SOD1 aggregation through two SMIR motifs and tubulin acetylation. J Biol Chem 288:15035–15045. https://doi.org/10.1074/jbc.M112.431957
Gan-Or Z, Ozelius LJ, Bar-Shira A et al (2013) The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease. Neurology 80:1606–1610. https://doi.org/10.1212/WNL.0b013e31828f180e
Ganley IG, Lam DH, Wang J et al (2009) ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 284:12297–12305. https://doi.org/10.1074/jbc.M900573200
Garcia-Alloza M, Borrelli LA, Rozkalne A et al (2007) Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J Neurochem 102:1095–1104. https://doi.org/10.1111/j.1471-4159.2007.04613.x
Gaugler J, James B, Johnson T et al (2016) 2016 Alzheimer’s disease facts and figures. Alzheimer’s Dementia 12:459–509. https://doi.org/10.1016/j.jalz.2016.03.001
Gaut JR, Hendershot LM (1993) The modification and assembly of proteins in the endoplasmic reticulum. Curr Opin Cell Biol 5:589–595. https://doi.org/10.1016/0955-0674(93)90127-C
Gegelashvili G, Dehnes Y, Danbolt NC, Schousboe A (2000) The high-affinity glutamate transporters GLT1, GLAST, and EAAT4 are regulated via different signalling mechanisms. Neurochem Int 37:163–170
Gleich K, Desmond MJ, Lee D et al (2013) Abnormal processing of autophagosomes in transformed B lymphocytes from SCARB2-deficient subjects. BioRes Open Access 2:40–46. https://doi.org/10.1089/biores.2012.0265
Goncalves S, Outeiro TF (2013) Assessing the subcellular dynamics of alpha-synuclein using photoactivation microscopy. Mol Neurobiol 47:1081–1092. https://doi.org/10.1007/s12035-013-8406-x
Gong CX, Liu F, Grundke-Iqbal I, Iqbal K (2005) Post-translational modifications of tau protein in Alzheimer’s disease. J Neural Transm 112:813–838. https://doi.org/10.1007/s00702-004-0221-0
Gong L, Yeh ETH (1999) Identification of the activating and conjugating enzymes of the NEDD8 conjugation pathway. J Biol Chem 274:12036–12042. https://doi.org/10.1074/jbc.274.17.12036
Gonzalez A, Valeiras M, Sidransky E, Tayebi N (2014) Lysosomal integral membrane protein-2: a new player in lysosome-related pathology. Mol Genet Metab 111:84–91. https://doi.org/10.1016/j.ymgme.2013.12.005
Goode A, Butler K, Long J et al (2016) Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD. Autophagy 12:1094–1104
Grogan PT, Sleder KD, Samadi AK et al (2013) Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways. Investig New Drugs 31:545–557. https://doi.org/10.1007/s10637-012-9888-5
Groll M, Ditzel L, Lowe J et al (1997) Structure of 20S proteasome from yeast at 2.4 A resolution. Nature 386:463–471. https://doi.org/10.1038/386463a0
Guareschi S, Cova E, Cereda C et al (2012) An over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1. Proc Natl Acad Sci U S A 109:5074–5079. https://doi.org/10.1073/pnas.1115402109
Guergnon J, Godet AN, Galioot A et al (2011) PP2A targeting by viral proteins: A widespread biological strategy from DNA/RNA tumor viruses to HIV-1. Biochim Biophys Acta Mol basis Dis 1812:1498–1507. https://doi.org/10.1016/j.bbadis.2011.07.001
Guo J-F, Yao L-Y, Sun Q-Y et al (2017) Identification of Ser465 as a novel PINK1 autophosphorylation site. Translat Neurodegener 6:34. https://doi.org/10.1186/s40035-017-0103-7
Guo X, Lv J, Lu J et al (2018) Protopanaxadiol derivative DDPU improves behavior and cognitive deficit in AD mice involving regulation of both ER stress and autophagy. Neuropharmacology 130:77–91. https://doi.org/10.1016/j.neuropharm.2017.11.033
Haas AL, Warms JV, Hershko A, Rose IA (1982) Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation. J Biol Chem 257:2543–2548
Hadano S, Otomo A, Kunita R et al (2010) Loss of ALS2/Alsin exacerbates motor dysfunction in a SOD1H46R-expressing mouse ALS model by disturbing endolysosomal trafficking. PLoS One 5:e9805
Harding HP, Zhang Y, Bertolotti A et al (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5:897–904. https://doi.org/10.1016/S1097-2765(00)80330-5
Harding RJ, Tong Y (2018) Proteostasis in Huntington’s disease: disease mechanisms and therapeutic opportunities. Acta Pharmacol Sin 39:754–769. https://doi.org/10.1038/aps.2018.11
Harjes P, Wanker EE (2003) The hunt for huntingtin function: interaction partners tell many different stories. Trends Biochem Sci 28:425–433. https://doi.org/10.1016/S0968-0004(03)00168-3
Harper PS (1992) Huntington disease and the abuse of genetics. Am J Hum Genet 50:460–464
Helferich AM, McLean PJ, Weishaupt JH, Danzer KM (2016) Commentary: alpha-synuclein interacts with SOD1 and promotes its oligomerization. J Neurol Neuromed 1:28–30
Henley JM, Carmichael RE, Wilkinson KA (2018) Extranuclear SUMOylation in neurons. Trends Neurosci 41:198–210. https://doi.org/10.1016/j.tins.2018.02.004
Hickey MA, Zhu C, Medvedeva V et al (2012a) Improvement of neuropathology and transcriptional deficits in CAG 140 knock-in mice supports a beneficial effect of dietary curcumin in Huntington’s disease. Mol Neurodegener 7:12. https://doi.org/10.1186/1750-1326-7-12
Hickey MA, Zhu C, Medvedeva V et al (2012b) Improvement of neuropathology and transcriptional deficits in CAG 140 knock-in mice supports a beneficial effect of dietary curcumin in Huntington’s disease. Mol Neurodegener 7:12. https://doi.org/10.1186/1750-1326-7-12
Hitomi J, Katayama T, Taniguchi M et al (2004) Apoptosis induced by endoplasmic reticulum stress depends on activation of caspase-3 via caspase-12. Neurosci Lett 357:127–130. https://doi.org/10.1016/j.neulet.2003.12.080
Hochstrasser M (1996) Ubiquitin-dependent protein degradation. Annu Rev Genet 30:405–439. https://doi.org/10.1146/annurev.genet.30.1.405
Hohfeld J, Jentsch S (1997) GrpE-like regulation of the hsc70 chaperone by the anti-apoptotic protein BAG-1. EMBO J 16:6209–6216. https://doi.org/10.1093/emboj/16.20.6209
Hol EM, van Leeuwen FW, Fischer DF (2005) The proteasome in Alzheimer’s disease and Parkinson’s disease: lessons from ubiquitin B+1. Trends Mol Med 11:488–495. https://doi.org/10.1016/j.molmed.2005.09.001
Hong L, Huang H-C, Jiang Z-F (2014) Relationship between amyloid-beta and the ubiquitin–proteasome system in Alzheimer’s disease. Neurol Res 36:276–282. https://doi.org/10.1179/1743132813Y.0000000288
Hooper C, Killick R, Lovestone S (2008) The GSK3 hypothesis of Alzheimer’s disease. J Neurochem 104:1433–1439. https://doi.org/10.1111/j.1471-4159.2007.05194.x
Hou Y, Guan J, Xu H et al (2015) Sestrin2 protects dopaminergic cells against rotenone Toxicity through AMPK-dependent autophagy activation. Mol Cell Biol 35:2740–2751. https://doi.org/10.1128/MCB.00285-15
Hu J-H, Zhang H, Wagey R et al (2003) Protein kinase and protein phosphatase expression in amyotrophic lateral sclerosis spinal cord. J Neurochem 85:432–442. https://doi.org/10.1046/j.1471-4159.2003.01670.x
Jana NR, Dikshit P, Goswami A et al (2005) Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes. J Biol Chem 280:11635–11640. https://doi.org/10.1074/jbc.M412042200
Jang W, Kim HJ, Li H et al (2014) 1,25-Dyhydroxyvitamin D(3) attenuates rotenone-induced neurotoxicity in SH-SY5Y cells through induction of autophagy. Biochem Biophys Res Commun 451:142–147. https://doi.org/10.1016/j.bbrc.2014.07.081
Jeong J-K, Moon M-H, Bae B-C et al (2012) Autophagy induced by resveratrol prevents human prion protein-mediated neurotoxicity. Neurosci Res 73:99–105
Jia H, Kast RJ, Steffan JS, Thomas EA (2012) Selective histone deacetylase (HDAC) inhibition imparts beneficial effects in Huntington’s disease mice: implications for the ubiquitin-proteasomal and autophagy systems. Hum Mol Genet 21:5280–5293. https://doi.org/10.1093/hmg/dds379
Jiang T-F, Zhang Y-J, Zhou H-Y et al (2013) Curcumin ameliorates the neurodegenerative pathology in A53T alpha-synuclein cell model of Parkinson’s disease through the downregulation of mTOR/p70S6K signaling and the recovery of macroautophagy. J NeuroImmune Pharmacol 8:356–369. https://doi.org/10.1007/s11481-012-9431-7
Jiang T, Yu J-T, Zhu X-C et al (2014) Temsirolimus promotes autophagic clearance of amyloid-β and provides protective effects in cellular and animal models of Alzheimer’s disease. Pharmacol Res 81:54–63. https://doi.org/10.1016/j.phrs.2014.02.008
Jinn S, Drolet RE, Cramer PE et al (2017) TMEM175 deficiency impairs lysosomal and mitochondrial function and increases alpha-synuclein aggregation. Proc Natl Acad Sci U S A 114:2389–2394. https://doi.org/10.1073/pnas.1616332114
Joshi V, Amanullah A, Upadhyay A et al (2016) A decade of boon or burden: what has the CHIP ever done for cellular protein quality control mechanism implicated in neurodegeneration and aging? Front Mol Neurosci 9:93. https://doi.org/10.3389/fnmol.2016.00093
Ju J-S, Fuentealba RA, Miller SE et al (2009) Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol 187:875–888
Kalia SK, Kalia LV, McLean PJ (2010) Molecular chaperones as rational drug targets for Parkinson’s disease therapeutics. CNS Neurol Disord Drug Targets 9:741–753
Kampinga HH, Bergink S (2016) Heat shock proteins as potential targets for protective strategies in neurodegeneration. Lancet Neurol 15:748–759. https://doi.org/10.1016/S1474-4422(16)00099-5
Kang J, Lemaire H-G, Unterbeck A et al (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733–736. https://doi.org/10.1038/325733a0
Kang U-B, Marto JA (2017) Leucine-rich repeat kinase 2 and Parkinson’s disease. Proteomics 17. https://doi.org/10.1002/pmic.201600092
Kaufman RJ (1999) Erratum: Stress signaling from the lumen of the endoplasmic reticulum: Coordination of gene transcriptional and translational controls (Genes and Development (1999) 13 (1211–1233)). Genes Dev 13:1898
Kaufman RJ (2002) Orchestrating the unfolded protein response in health and disease. J Clin Investig 110:1389–1398. https://doi.org/10.1172/JCI0216886
Keck S, Nitsch R, Grune T, Ullrich O (2003) Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer’s disease. J Neurochem 85:115–122. https://doi.org/10.1046/j.1471-4159.2003.01642.x
Kelley WL (1999) Molecular chaperones: how J domains turn on Hsp70s. Curr Biol 9:R305–R308. https://doi.org/10.1016/s0960-9822(99)80185-7
Kidd SK, Schneider JS (2011) Protective effects of valproic acid on the nigrostriatal dopamine system in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Neuroscience 194:189–194. https://doi.org/10.1016/j.neuroscience.2011.08.010
Klein C, Djarmati A, Hedrich K et al (2005) PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism. Eur J Hum Genet 13:1086–1093. https://doi.org/10.1038/sj.ejhg.5201455
Klucken J, Shin Y, Masliah E et al (2004) Hsp70 Reduces alpha-synuclein aggregation and toxicity. J Biol Chem 279:25497–25502. https://doi.org/10.1074/jbc.M400255200
Koike H, Tomioka S, Sorimachi H et al (1999) Membrane-anchored metalloprotease MDC9 has an α-secretase activity responsible for processing the amyloid precursor protein. Biochem J 343:371–375. https://doi.org/10.1042/0264-6021:3430371
Korvatska O, Strand NS, Berndt JD et al (2013) Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS). Hum Mol Genet 22:3259–3268. https://doi.org/10.1093/hmg/ddt180
Kurtishi A, Rosen B, Patil KS et al (2019) Cellular proteostasis in neurodegeneration. Mol Neurobiol 56:3676–3689. https://doi.org/10.1007/s12035-018-1334-z
Labbadia J, Morimoto RI (2014) Proteostasis and longevity: when does aging really begin ? 7. https://doi.org/10.12703/P6-7
Laifenfeld D, Patzek LJ, McPhie DL et al (2007) Rab5 mediates an amyloid precursor protein signaling pathway that leads to apoptosis. J Neurosci 27:7141–7153. https://doi.org/10.1523/JNEUROSCI.4599-06.2007
Lamanauskas N, Nistri A (2008) Riluzole blocks persistent Na+ and Ca2+ currents and modulates release of glutamate via presynaptic NMDA receptors on neonatal rat hypoglossal motoneurons in vitro. Eur J Neurosci 27:2501–2514
Lambon Ralph MA, Patterson K, Graham N et al (2003) Homogeneity and heterogeneity in mild cognitive impairment and Alzheimer’s disease: a cross-sectional and longitudinal study of 55 cases. Brain 126:2350–2362. https://doi.org/10.1093/brain/awg236
Lan D-M, Liu F-T, Zhao J et al (2012) Effect of trehalose on PC12 cells overexpressing wild-type or A53T mutant alpha-synuclein. Neurochem Res 37:2025–2032. https://doi.org/10.1007/s11064-012-0823-0
Landles C, Bates GP (2004) Huntingtin and the molecular pathogenesis of Huntington’s disease. EMBO Rep 5:958–963. https://doi.org/10.1038/sj.embor.7400250
Lang AE, Lozano AM (1998) Parkinson’s disease. First of two parts. N Engl J Med 339:1044–1053. https://doi.org/10.1056/NEJM199810083391506
Lee M-R, Lee D, Shin SK et al (2008) Inhibition of APP intracellular domain (AICD) transcriptional activity via covalent conjugation with Nedd8. Biochem Biophys Res Commun 366:976–981. https://doi.org/10.1016/j.bbrc.2007.12.066
Lesage S, Drouet V, Majounie E et al (2016) Loss of VPS13C function in autosomal-recessive parkinsonism causes mitochondrial dysfunction and increases PINK1/Parkin-dependent mitophagy. Am J Hum Genet 98:500–513. https://doi.org/10.1016/j.ajhg.2016.01.014
Li M, Damuni Z (1998) I1PP2A and I2PP2A BT - protein phosphatase protocols. In: Ludlow JW (ed). Humana Press, Totowa, NJ, pp 59–66
Li W, Li J, Bao J (2012) Microautophagy: lesser-known self-eating. Cell Mol Life Sci 69:1125–1136. https://doi.org/10.1007/s00018-011-0865-5
Lindsten K, De Vrij FMS, Verhoef LGGC et al (2002) Mutant ubiquitin found in neurodegenerative disorders is a ubiquitin fusion degradation substrate that blocks proteasomal degradation. J Cell Biol 157:417–427. https://doi.org/10.1083/jcb.200111034
Liu J, Chen M, Wang X, et al (2016) Piperine induces autophagy by enhancing protein phosphotase 2A activity in a rotenone-induced Parkinson’s disease model. Oncotarget 7:60823–60843. https://doi.org/10.18632/oncotarget.11661
Liu X, Betzenhauser MJ, Reiken S et al (2012) Role of leaky neuronal ryanodine receptors in stress-induced cognitive dysfunction. Cell 150:1055–1067. https://doi.org/10.1016/j.cell.2012.06.052
Llorens-Martín M, Jurado J, Hernández F, Ávila J (2014) GSK-3β, a pivotal kinase in Alzheimer disease. Front Mol Neurosci 7:1–11. https://doi.org/10.3389/fnmol.2014.00046
Loffler AS, Alers S, Dieterle AM et al (2011) Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop. Autophagy 7:696–706. https://doi.org/10.4161/auto.7.7.15451
Lu X-H, Fleming SM, Meurers B et al (2009) Bacterial artificial chromosome transgenic mice expressing a truncated mutant parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of proteinase K-resistant alpha-synuclein. J Neurosci 29:1962–1976. https://doi.org/10.1523/JNEUROSCI.5351-08.2009
Ly PTT, Wu Y, Zou H et al (2013) Inhibition of GSK3 b-mediated BACE1 expression reduces Alzheimer-associated phenotypes Find the latest version: Inhibition of GSK3 β-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J Clin Invest 123:224–235. https://doi.org/10.1172/JCI64516.224
Ma Q-L, Zuo X, Yang F et al (2013) Curcumin suppresses soluble Tau dimers and corrects molecular chaperone, synaptic, and behavioral deficits in aged human Tau transgenic mice. J Biol Chem 288:4056–4065. https://doi.org/10.1074/jbc.M112.393751
Ma Y, Hendershot LM (2004) ER chaperone functions during normal and stress conditions. J Chem Neuroanat 28:51–65. https://doi.org/10.1016/j.jchemneu.2003.08.007
Mahul-Mellier A-L, Fauvet B, Gysbers A et al (2014) c-Abl phosphorylates alpha-synuclein and regulates its degradation: implication for alpha-synuclein clearance and contribution to the pathogenesis of Parkinson’s disease. Hum Mol Genet 23:2858–2879. https://doi.org/10.1093/hmg/ddt674
Maiti P, Manna J, Veleri S, Frautschy S (2014) Molecular chaperone dysfunction in neurodegenerative diseases and effects of curcumin. Biomed Res Int 2014:1–14. https://doi.org/10.1155/2014/495091
Mak SK, McCormack AL, Manning-Bog AB et al (2010) Lysosomal degradation of alpha-synuclein in vivo. J Biol Chem 285:13621–13629. https://doi.org/10.1074/jbc.M109.074617
Maraganore DM, Lesnick TG, Elbaz A et al (2004) UCHL1 is a Parkinson’s disease susceptibility gene. Ann Neurol 55:512–521. https://doi.org/10.1002/ana.20017
Maria Cuervo A, Stefanis L, Fredenburg R et al (2004) Impaired degradation of mutant-synuclein by chaperone-mediated autophagy. Science (New York, NY) 305:1292–1295. https://doi.org/10.1126/science.1101738
Marrone L, Drexler HCA, Wang J et al (2019) FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy. Acta Neuropathol 138:67–84. https://doi.org/10.1007/s00401-019-01998-x
Martinez-Vicente M, Talloczy Z, Wong E et al (2010) Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat Neurosci 13:567–576. https://doi.org/10.1038/nn.2528
Matsumoto G, Wada K, Okuno M et al (2011) Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell 44:279–289. https://doi.org/10.1016/j.molcel.2011.07.039
Matts RL, Brandt GEL, Lu Y et al (2011) A systematic protocol for the characterization of Hsp90 modulators. Bioorg Med Chem 19:684–692. https://doi.org/10.1016/j.bmc.2010.10.029
McLean PJ, Kawamata H, Shariff S et al (2002) TorsinA and heat shock proteins act as molecular chaperones: suppression of alpha-synuclein aggregation. J Neurochem 83:846–854. https://doi.org/10.1046/j.1471-4159.2002.01190.x
Meacham GC, Patterson C, Zhang W et al (2001) The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nat Cell Biol 3:100–105. https://doi.org/10.1038/35050509
Mealer RG, Murray AJ, Shahani N et al (2014) Rhes, a striatal-selective protein implicated in huntington disease, binds beclin-1 and activates autophagy. J Biol Chem 289:3547–3554. https://doi.org/10.1074/jbc.M113.536912
Medinas DB, Valenzuela V, Hetz C (2017) Proteostasis disturbance in amyotrophic lateral sclerosis. Hum Mol Genet 26:R91–R104
Meng T, Lin S, Zhuang H et al (2019) Recent progress in the role of autophagy in neurological diseases. Cell Stress 3:141–161. https://doi.org/10.15698/cst2019.05.186
Mi K, Johnson G (2006) The role of Tau phosphorylation in the pathogenesis of Alzheimers disease. Curr Alzheimer Res 3:449–463. https://doi.org/10.2174/156720506779025279
Michalik A, Van Broeckhoven C (2004) Proteasome degrades soluble expanded polyglutamine completely and efficiently. Neurobiol Dis 16:202–211. https://doi.org/10.1016/j.nbd.2003.12.020
Migdalska-richards A, Daly L, Bezard E, Schapira AH V (2016) Ambroxol effects in glucocerebrosidase and a-synuclein transgenic mice. https://doi.org/10.1002/ana.24790
Miller VM, Nelson RF, Gouvion CM et al (2005) CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo. J Neurosci 25:9152–9161. https://doi.org/10.1523/JNEUROSCI.3001-05.2005
More SV, Choi D-K (2015) Promising cannabinoid-based therapies for Parkinson’s disease: motor symptoms to neuroprotection. Mol Neurodegener 10:17. https://doi.org/10.1186/s13024-015-0012-0
Morimoto RI, Cuervo AM (2014) Proteostasis and the aging proteome in health and disease. J Gerontol A Biol Sci Med Sci 69 Suppl 1:S33–S38. https://doi.org/10.1093/gerona/glu049
Morreale FE, Walden H (2016) Types of ubiquitin ligases. Cell 165:248–248.e1. https://doi.org/10.1016/j.cell.2016.03.003
Murata H, Sakaguchi M, Kataoka K, Huh N-H (2013) SARM1 and TRAF6 bind to and stabilize PINK1 on depolarized mitochondria. Mol Biol Cell 24:2772–2784. https://doi.org/10.1091/mbc.E13-01-0016
Murata S, Minami Y, Minami M et al (2001) CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein. EMBO Rep 2:1133–1138. https://doi.org/10.1093/embo-reports/kve246
Murphy KE, Gysbers AM, Abbott SK et al (2014) Reduced glucocerebrosidase is associated with increased alpha-synuclein in sporadic Parkinson’s disease. Brain 137:834–848. https://doi.org/10.1093/brain/awt367
Murphy KE, Gysbers AM, Abbott SK et al (2015) Lysosomal-associated membrane protein 2 isoforms are differentially affected in early Parkinson’s disease. Mov Disord 30:1639–1647. https://doi.org/10.1002/mds.26141
Murphy MP, Iii HL (2010) AD and beta amyloid peptide. J Alzheimers Dis 19:1–17. https://doi.org/10.3233/JAD-2010-1221.Alzheimer
Nagoshi N, Nakashima H, Fehlings M (2015) Riluzole as a neuroprotective drug for spinal cord injury: from bench to bedside. Molecules 20:7775–7789
Neef DW, Jaeger AM, Thiele DJ (2011) Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases. Nat Rev Drug Discov 10:930–944. https://doi.org/10.1038/nrd3453
Nillegoda NB, Bukau B (2015) Metazoan Hsp70-based protein disaggregases: emergence and mechanisms. Front Mol Biosci 2:57. https://doi.org/10.3389/fmolb.2015.00057
Nilsson P, Loganathan K, Sekiguchi M et al (2013) Aβ secretion and plaque formation depend on autophagy. Cell Rep 5:61–69. https://doi.org/10.1016/j.celrep.2013.08.042
Nixon RA, Wegiel J, Kumar A et al (2005) Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 64:113–122. https://doi.org/10.1093/jnen/64.2.113
Oddo S (2008) The ubiquitin-proteasome system in Alzheimer’s disease. J Cell Mol Med 12:363–373. https://doi.org/10.1111/j.1582-4934.2008.00276.x
Oh S-M, Liu Z, Okada M et al (2010) Ebp1 sumoylation, regulated by TLS/FUS E3 ligase, is required for its anti-proliferative activity. Oncogene 29:1017–1030. https://doi.org/10.1038/onc.2009.411
Oh S, Hong HS, Hwang E et al (2005) Amyloid peptide attenuates the proteasome activity in neuronal cells. Mech Ageing Dev 126:1292–1299. https://doi.org/10.1016/j.mad.2005.07.006
Okun I, Tkachenko SE, Khvat A et al (2010) From anti-allergic to anti-Alzheimer’s: molecular pharmacology of Dimebon. Curr Alzheimer Res 7:97–112. https://doi.org/10.2174/156720510790691100
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 33:339–348. https://doi.org/10.3233/JAD-2012-121072
Orlacchio A, Babalini C, Borreca A et al (2010) SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain 133:591–598
Ortega Z, Lucas JJ (2014) Ubiquitin-proteasome system involvement in Huntington’s disease. Front Mol Neurosci 7. https://doi.org/10.3389/fnmol.2014.00077
Osaka M, Ito D, Yagi T et al (2014) Evidence of a link between ubiquilin 2 and optineurin in amyotrophic lateral sclerosis. Hum Mol Genet 24:1617–1629
Pasinetti GM (2001) Use of cDNA microarray in the search for molecular markers involved in the onset of Alzheimer’s disease dementia. J Neurosci Res 65:471–476. https://doi.org/10.1002/jnr.1176
Perrotta C, Cervia D, De Palma C et al (2015) The emerging role of acid sphingomyelinase in autophagy. Apoptosis 20:635–644. https://doi.org/10.1007/s10495-015-1101-9
Perry G, Friedman R, Shawt G (1987) neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. Proc Natl Acad Sci U S A 84:3033–3036
Perry RJ, Hodges JR (1999) Attention and executive deficits in Alzheimer’s disease. A critical review. Brain 122:383–404. https://doi.org/10.1093/brain/122.3.383
Petrucelli L, Dickson D, Kehoe K et al (2004) CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet 13:703–714. https://doi.org/10.1093/hmg/ddh083
Phiel CJ, Wilson CA, Lee VM-Y, Klein PS (2003) GSK-3α regulates production of Alzheimer’s disease amyloid-β peptides. Nature 423:435–439. https://doi.org/10.1038/nature01640
Pickart CM (2001) Mechanisms underlying ubiquitination. Annu Rev Biochem 70:503–533. https://doi.org/10.1146/annurev.biochem.70.1.503
Pickrell AM, Youle RJ (2015) The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron 85:257–273. https://doi.org/10.1016/j.neuron.2014.12.007
Pierzynowska K, Gaffke L, Cyske Z et al (2018) Autophagy stimulation as a promising approach in treatment of neurodegenerative diseases. Metab Brain Dis 33:989–1008. https://doi.org/10.1007/s11011-018-0214-6
Plattner F, Angelo M, Giese KP (2006) The roles of cyclin-dependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation. J Biol Chem 281:25457–25465. https://doi.org/10.1074/jbc.M603469200
Podvin S, Reardon HT, Yin K et al (2019) Multiple clinical features of Huntington’s disease correlate with mutant HTT gene CAG repeat lengths and neurodegeneration. J Neurol 266:551–564. https://doi.org/10.1007/s00415-018-8940-6
Polson HEJ, de Lartigue J, Rigden DJ et al (2010) Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation. Autophagy 6:506–522. https://doi.org/10.4161/auto.6.4.11863
Powers ET, Balch WE (2013) Diversity in the origins of proteostasis networks--a driver for protein function in evolution. Nat Rev Mol Cell Biol 14:237–248. https://doi.org/10.1038/nrm3542
Powers ET, Morimoto RI, Dillin A et al (2009) Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem 78:959–991. https://doi.org/10.1146/annurev.biochem.052308.114844
Powers MV, Workman P (2007) Inhibitors of the heat shock response: biology and pharmacology. FEBS Lett 581:3758–3769. https://doi.org/10.1016/j.febslet.2007.05.040
Putcha P, Danzer KM, Kranich LR, et al (2009) Number of Text Pages : https://doi.org/10.1124/jpet.109.158436
Rampelt H, Kirstein-Miles J, Nillegoda NB et al (2012) Metazoan Hsp70 machines use Hsp110 to power protein disaggregation. EMBO J 31:4221–4235. https://doi.org/10.1038/emboj.2012.264
Rankin CA, Sun Q, Gamblin TC (2007) Tau phosphorylation by GSK-3ß promotes tangle-like filament morphology. Mol Neurodegener 2:1–14. https://doi.org/10.1186/1750-1326-2-12
Rao RV, Ellerby HM, Bredesen DE (2004) Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ 11:372–380. https://doi.org/10.1038/sj.cdd.4401378
Ravid T, Hochstrasser M (2008) Diversity of degradation signals in the ubiquitin-proteasome system. Nat Rev Mol Cell Biol 9:679–690. https://doi.org/10.1038/nrm2468
Ravikumar B, Imarisio S, Sarkar S et al (2008) Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease. J Cell Sci 121:1649–1660
Ravikumar B, Vacher C, Berger Z et al (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36:585–595. https://doi.org/10.1038/ng1362
Redler RL, Wilcox KC, Proctor EA et al (2011) Glutathionylation at Cys-111 induces dissociation of wild type and FALS mutant SOD1 dimers. Biochemistry 50:7057–7066. https://doi.org/10.1021/bi200614y
Reis SD, Pinho BR, Oliveira JMA (2017) Modulation of molecular chaperones in Huntington’s disease and other polyglutamine disorders. Mol Neurobiol 54:5829–5854. https://doi.org/10.1007/s12035-016-0120-z
Ren Y, Chen J, Wu X et al (2018) Role of c-Abl-GSK3beta signaling in MPP+-induced autophagy-lysosomal dysfunction. Toxicol Sci 165:232–243. https://doi.org/10.1093/toxsci/kfy155
Ricobaraza A, Cuadrado-Tejedor M, Perez-Mediavilla A et al (2009) Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer’s disease mouse model. Neuropsychopharmacology 34:1721–1732. https://doi.org/10.1038/npp.2008.229
Ringman JM, Frautschy SA, Teng E et al (2012) Oral curcumin for Alzheimer’s disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Alzheimers Res Ther 4:43. https://doi.org/10.1186/alzrt146
Rochet J-C (2007) Novel therapeutic strategies for the treatment of protein-misfolding diseases. Expert Rev Mol Med 9:1–34. https://doi.org/10.1017/S1462399407000385
Rodríguez-Navarro JA, Rodríguez L, Casarejos MJ et al (2010) Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation. Neurobiol Dis 39:423–438. https://doi.org/10.1016/j.nbd.2010.05.014
Romani-Aumedes J, Canal M, Martin-Flores N et al (2014) Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson’s disease. Cell Death Dis 5:e1364. https://doi.org/10.1038/cddis.2014.333
Rose C, Menzies FM, Renna M et al (2010) Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington’s disease. Hum Mol Genet 19:2144–2153. https://doi.org/10.1093/hmg/ddq093
Rosen DR, Siddique T, Patterson D et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59
Rosenbusch KE, Kortholt A (2016) Activation mechanism of LRRK2 and its cellular functions in Parkinson’s disease. Parkinson’s Dis 2016:7351985. https://doi.org/10.1155/2016/7351985
Rubinsztein DC, Marino G, Kroemer G (2011) Autophagy and aging. Cell 146:682–695. https://doi.org/10.1016/j.cell.2011.07.030
Rui Y-N, Xu Z, Patel B et al (2015) Huntingtin functions as a scaffold for selective macroautophagy. Nat Cell Biol 17:262–275. https://doi.org/10.1038/ncb3101
Saha S, Ash PEA, Gowda V et al (2015) Mutations in LRRK2 potentiate age-related impairment of autophagic flux. Mol Neurodegener 10:26. https://doi.org/10.1186/s13024-015-0022-y
Sakahira H, Breuer P, Hayer-Hartl MK, Hartl FU (2002) Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. Proc Natl Acad Sci 99:16412–16418. https://doi.org/10.1073/pnas.182426899
Sarkar M, Kuret J, Lee G (2008a) Two motifs within the tau microtubule-binding domain mediate its association with the hsc70 molecular chaperone. J Neurosci Res 86:2763–2773. https://doi.org/10.1002/jnr.21721
Sarkar S, Krishna G, Imarisio S et al (2007) A rational mechanism for combination treatment of Huntington’s disease using lithium and rapamycin. Hum Mol Genet 17:170–178
Sarkar S, Krishna G, Imarisio S et al (2008b) A rational mechanism for combination treatment of Huntington’s disease using lithium and rapamycin. Hum Mol Genet 17:170–178. https://doi.org/10.1093/hmg/ddm294
Saxena S, Cabuy E, Caroni P (2009) A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nat Neurosci 12:627–636. https://doi.org/10.1038/nn.2297
Schaeffer V, Lavenir I, Ozcelik S et al (2012) Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy. Brain 135:2169–2177. https://doi.org/10.1093/brain/aws143
Scheper W, Nijholt DAT, Hoozemans JJM (2011) The unfolded protein response and proteostasis in Alzheimer disease: Preferential activation of autophagy by endoplasmic reticulum stress. Autophagy 7:910–911. https://doi.org/10.4161/auto.7.8.15761
Schonhoff CM, Matsuoka M, Tummala H et al (2006) S-nitrosothiol depletion in amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 103:2404–2409. https://doi.org/10.1073/pnas.0507243103
Sellier C, Campanari M, Corbier CJ et al (2016) Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. EMBO J 35:1276–1297
Setsuie R, Wang Y-L, Mochizuki H et al (2007) Dopaminergic neuronal loss in transgenic mice expressing the Parkinson’s disease-associated UCH-L1 I93M mutant. Neurochem Int 50:119–129. https://doi.org/10.1016/j.neuint.2006.07.015
Seyfried NT, Gozal YM, Dammer EB et al (2010) Multiplex SILAC analysis of a cellular TDP-43 proteinopathy model reveals protein inclusions associated with SUMOylation and diverse polyubiquitin chains. Mol Cell Proteomics 9:705–718. https://doi.org/10.1074/mcp.M800390-MCP200
Shan X, Vocadlo DJ, Krieger C (2012) Reduced protein O-glycosylation in the nervous system of the mutant SOD1 transgenic mouse model of amyotrophic lateral sclerosis. Neurosci Lett 516:296–301. https://doi.org/10.1016/j.neulet.2012.04.018
Shaw BF, Lelie HL, Durazo A et al (2008) Detergent-insoluble aggregates associated with amyotrophic lateral sclerosis in transgenic mice contain primarily full-length, unmodified superoxide dismutase-1. J Biol Chem 283:8340–8350. https://doi.org/10.1074/jbc.M707751200
Shen X, Zhang K, Kaufman RJ (2004) The unfolded protein response - a stress signaling pathway of the endoplasmic reticulum. J Chem Neuroanat 28:79–92. https://doi.org/10.1016/j.jchemneu.2004.02.006
Shibata M, Lu T, Furuya T et al (2006) Regulation of intracellular accumulation of mutant huntingtin by beclin 1. J Biol Chem 281:14474–14485. https://doi.org/10.1074/jbc.M600364200
Shirotani K, Tsubuki S, Iwata N et al (2001) Neprilysin degrades both amyloid β peptides 1–40 and 1–42 most rapidly and efficiently among thiorphan- and phosphoramidon-sensitive endopeptidases. J Biol Chem 276:21895–21901. https://doi.org/10.1074/jbc.M008511200
Sidrauski C, Walter P (1997) The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Cell 90:1031–1039. https://doi.org/10.1016/S0092-8674(00)80369-4
Sontag E, Nunbhakdi-Craig V, Lee G et al (1996) Regulation of the phosphorylation state and microtubule-binding activity of tau by protein phosphatase 2A. Neuron 17:1201–1207. https://doi.org/10.1016/S0896-6273(00)80250-0
Sóti C, Csermely P (2000) Molecular chaperones and the aging process. Biogerontology 1:225–233
Spilman P, Podlutskaya N, Hart MJ et al (2010) Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer’s disease. PLoS ONE 5:e9979
Spratt DE, Walden H, Shaw GS (2014) RBR E3 ubiquitin ligases: new structures, new insights, new questions. Biochem J 458:421–437. https://doi.org/10.1042/BJ20140006
Stanic J, Mellone M, Cirnaru MD et al (2016) LRRK2 phosphorylation level correlates with abnormal motor behaviour in an experimental model of levodopa-induced dyskinesias. Molec Brain 9:53. https://doi.org/10.1186/s13041-016-0234-2
Steele JW, Lachenmayer ML, Ju S et al (2013) Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer’s mouse model. Mol Psychiatry 18:889–897. https://doi.org/10.1038/mp.2012.106
Swingle M, Ni L, Honkanen RE (2007) Small-molecule inhibitors of Ser/Thr protein phosphatases. Protein Phosphatase Protocols 365:23–38
Tai H-C, Besche H, Goldberg AL, Schuman EM (2010) Characterization of the brain 26S proteasome and its interacting proteins. Front Mol Neurosci 3. https://doi.org/10.3389/fnmol.2010.00012
Takalo M, Haapasalo A, Natunen T et al (2013) Targeting ubiquilin-1 in Alzheimer’s disease. Expert Opin Ther Targets 17:795–810. https://doi.org/10.1517/14728222.2013.791284
Takuma K, Du Yan SS, Stern DM, Yamada K (2005) Mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis in Alzheimer’s disease. J Pharmacol Sci 97:312–316. https://doi.org/10.1254/jphs.CPJ04006X
Taldone T, Chiosis G (2009) Purine-scaffold Hsp90 inhibitors. Curr Top Med Chem 9:1436–1446. https://doi.org/10.2174/156802609789895737
Tellez-Nagel I, Johnson AB, Terry RD (1974) Studies on brain biopsies of patients with Huntingtonʼs chorea. J Neuropathol Exp Neurol 33:308–332. https://doi.org/10.1097/00005072-197404000-00008
Teske BF, Wek SA, Bunpo P et al (2011) The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress. Mol Biol Cell 22:4390–4405. https://doi.org/10.1091/mbc.E11-06-0510
Thakur P, Nehru B (2014) Long-term heat shock proteins (HSPs) induction by carbenoxolone improves hallmark features of Parkinson’s disease in a rotenone-based model. Neuropharmacology 79:190–200. https://doi.org/10.1016/j.neuropharm.2013.11.016
Tian G, Lai L, Guo H et al (2007) Translational control of glial glutamate transporter EAAT2 expression. J Biol Chem 282:1727–1737. https://doi.org/10.1074/jbc.M609822200
Todi SV, Paulson HL (2011) Balancing act: deubiquitinating enzymes in the nervous system. Trends Neurosci 34:370–382. https://doi.org/10.1016/j.tins.2011.05.004
Tokuda E, Marklund SL, Furukawa Y (2019) Prion-like properties of misfolded Cu/Zn-superoxide dismutase in amyotrophic lateral sclerosis: update and perspectives. Yakugaku Zasshi 139:1015–1019. https://doi.org/10.1248/yakushi.18-00165-5
Tresse E, Salomons FA, Vesa J et al (2010) VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. Autophagy 6:217–227
Tseng BP, Green KN, Chan JL et al (2008) Aβ inhibits the proteasome and enhances amyloid and tau accumulation. Neurobiol Aging 29:1607–1618. https://doi.org/10.1016/j.neurobiolaging.2007.04.014
Tyzack GE, Luisier R, Taha DM et al (2019) Widespread FUS mislocalization is a molecular hallmark of amyotrophic lateral sclerosis. Brain. https://doi.org/10.1093/brain/awz217
Unterberger U, Höftberger R, Gelpi E et al (2006) Endoplasmic reticulum stress features are prominent in Alzheimer disease but not in prion diseases in vivo. J Neuropathol Exp Neurol 65:348–357. https://doi.org/10.1097/01.jnen.0000218445.30535.6f
Usenovic M, Tresse E, Mazzulli JR et al (2013) Deficiency of ATP13A2 leads to lysosomal dysfunction, alpha-synuclein accumulation, and neurotoxicity. J Neurosci 32:4240–4246. https://doi.org/10.1523/JNEUROSCI.5575-11.2012
Van der Vlies D, Makkinje M, Jansens A et al (2003) Oxidation of ER resident proteins upon oxidative stress: effects of altering cellular redox/antioxidant status and implications for protein maturation. Antioxid Redox Signal 5:381–387. https://doi.org/10.1089/152308603768295113
Van Leeuwen F (1998) frameshifts mutants of APP and ubiquitin b in AD patients. Science 279:242–246
Venkatraman P, Wetzel R, Tanaka M et al (2004) Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins. Mol Cell 14:95–104
Voronkov M, Braithwaite SP, Stock JB (2011) Phosphoprotein phosphatase 2A: a novel druggable target for Alzheimer’s disease. Future Med Chem 3:821–833. https://doi.org/10.4155/fmc.11.47
Waelter S, Boeddrich A, Lurz R et al (2001) Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol Biol Cell 12:1393–1407. https://doi.org/10.1091/mbc.12.5.1393
Wagner U, Utton M, Gallo JM, Miller CCJ (1996) Cellular phosphorylation of tau by GSK-3β influences tau binding to microtubules and microtubule organisation. J Cell Sci 109:1537–1543
Walker LC, LeVine H (2000) The cerebral proteopathies: neurodegenerative disorders of protein conformation and assembly. Mol Neurobiol 21:83–95. https://doi.org/10.1385/MN:21:1-2:083
Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science (New York, NY) 334:1081–1086. https://doi.org/10.1126/science.1209038
Warrick JM, Morabito LM, Bilen J et al (2005) Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism. Mol Cell 18:37–48. https://doi.org/10.1016/j.molcel.2005.02.030
Waxman EA, Giasson BI (2011) Characterization of kinases involved in the phosphorylation of aggregated alpha-synuclein. J Neurosci Res 89:231–247. https://doi.org/10.1002/jnr.22537
Webb JL, Ravikumar B, Atkins J et al (2003) Alpha-synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278:25009–25013. https://doi.org/10.1074/jbc.M300227200
Webster CP, Smith EF, Bauer CS et al (2016) The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J 35:1656–1676
Wijesekera LC, Leigh PN (2009) Amyotrophic lateral sclerosis. Orphanet J Rare Dis 4:3
Williamson MP (1994) The structure and function of proline-rich regions in proteins. Biochem J 297:249–260. https://doi.org/10.1042/bj2970249
Williamson TL, Cleveland DW (1999) Slowing of axonal transport is a very early event in the toxicity of ALS–linked SOD1 mutants to motor neurons. Nat Neurosci 2:50
Wilson RS, Segawa E, Boyle PA et al (2012) Psychology and aging the natural history of cognitive decline in Alzheimer’s disease. Nat Hist Cognit Decline Alzheimer’s Dis 27. https://doi.org/10.1037/a0029857
Winborn BJ, Travis SM, Todi SV et al (2008) The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains. J Biol Chem 283:26436–26443. https://doi.org/10.1074/jbc.M803692200
Wong YC, Holzbaur ELF (2014) Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc Natl Acad Sci 111:E4439–E4448
Wu Y, Li X, Zhu JX et al (2011) Resveratrol-activated AMPK/SIRT1/autophagy in cellular models of Parkinson’s disease. Neuro-Signals 19:163–174. https://doi.org/10.1159/000328516
Xu C, Bailly-Maitre B, Reed JC (2005) Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 115:2656–2664. https://doi.org/10.1172/JCI26373
Xu Y, Chen Y, Zhang P et al (2008) Structure of a protein phosphatase 2A holoenzyme: insights into B55-mediated Tau dephosphorylation. Mol Cell 31:873–885. https://doi.org/10.1016/j.molcel.2008.08.006
Xue X, Wang L-R, Sato Y et al (2014) Single-walled carbon nanotubes alleviate autophagic/lysosomal defects in primary glia from a mouse model of Alzheimer’s disease. Nano Lett 14:5110–5117. https://doi.org/10.1021/nl501839q
Yang G, Li J, Cai Y et al (2018) Glycyrrhizic acid alleviates 6-hydroxydopamine and corticosterone-induced neurotoxicity in SH-SY5Y cells through modulating autophagy. Neurochem Res 43:1914–1926. https://doi.org/10.1007/s11064-018-2609-5
Yang Y, Hentati A, Deng H-X et al (2001) The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet 29:160
Yang Y, Turner RS, Gaut JR (1998) The chaperone BiP/GRP78 binds to amyloid precursor protein and decreases Aβ40 and Aβ42 secretion. J Biol Chem 273:25552–25555. https://doi.org/10.1074/jbc.273.40.25552
Yang Z, Klionsky DJ (2010) Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 22:124–131. https://doi.org/10.1016/j.ceb.2009.11.014
Yao C, El Khoury R, Wang W et al (2010) LRRK2-mediated neurodegeneration and dysfunction of dopaminergic neurons in a Caenorhabditis elegans model of Parkinson’s disease. Neurobiol Dis 40:73–81. https://doi.org/10.1016/j.nbd.2010.04.002
Yi J, Zhang L, Tang B et al (2013) Sodium valproate alleviates neurodegeneration in SCA3/MJD via suppressing apoptosis and rescuing the hypoacetylation levels of histone H3 and H4. PLoS One 8:e54792. https://doi.org/10.1371/journal.pone.0054792
Yoo Y-E, Ko C-P (2011) Treatment with trichostatin A initiated after disease onset delays disease progression and increases survival in a mouse model of amyotrophic lateral sclerosis. Exp Neurol 231:147–159. https://doi.org/10.1016/j.expneurol.2011.06.003
Yoshida H, Matsui T, Yamamoto A et al (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor phorylation, the activated Ire1p specifically cleaves HAC1 precursor mRNA to remove an intron of 252 nucle-otides. The cleaved 5 and. Cell 107:881–891
Yupin C, Zhang D, Liao Z, et al (2015) Anti-oxidant polydatin (piceid) protects against substantia nigral motor degeneration in multiple rodent models of Parkinson’s disease. Molecular Neurodegeneration 10:. https://doi.org/10.1186/1750-1326-10-4
Zagami CJ, Beart PM, Wallis N et al (2009) Oxidative and excitotoxic insults exert differential effects on spinal motoneurons and astrocytic glutamate transporters: Implications for the role of astrogliosis in amyotrophic lateral sclerosis. Glia 57:119–135. https://doi.org/10.1002/glia.20739
Zagami CJ, O’Shea RD, Lau CL et al (2005) Regulation of glutamate transporters in astrocytes: evidence for a relationship between transporter expression and astrocytic phenotype. Neurotox Res 7:143–149
Zarei S, Carr K, Reiley L, et al (2015) A comprehensive review of amyotrophic lateral sclerosis. Surgical neurology international 6:
Zavodszky E, Seaman MNJ, Moreau K et al (2014) Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy. Nat Commun 5:3828. https://doi.org/10.1038/ncomms4828
Zeng L, Tallaksen-Greene SJ, Wang B et al (2013) The de-ubiquitinating enzyme ataxin-3 does not modulate disease progression in a knock-in mouse model of Huntington disease. J Huntington’s Dis 2:201–215. https://doi.org/10.3233/JHD-130058
Zhang H, Ma Q, Zhang YW, Xu H (2012) Proteolytic processing of Alzheimer’s β-amyloid precursor protein. J Neurochem 120:9–21. https://doi.org/10.1111/j.1471-4159.2011.07519.x
Zhang S, Hedskog L, Petersen CAH et al (2010) Dimebon (latrepirdine) enhances mitochondrial function and protects neuronal cells from death. J Alzheimer’s Dis 21:389–402. https://doi.org/10.3233/JAD-2010-100174
Zhang S, Wang Z, Cai F et al (2017) BACE1 cleavage site selection critical for amyloidogenesis and Alzheimer’s pathogenesis. J Neurosci 37:6915–6925. https://doi.org/10.1523/JNEUROSCI.0340-17.2017
Zhang X, Chen S, Song L et al (2014) MTOR-independent, autophagic enhancer trehalose prolongs motor neuron survival and ameliorates the autophagic flux defect in a mouse model of amyotrophic lateral sclerosis. Autophagy 10:588–602
Zhang Y-Q, Sarge KD (2007) Celastrol inhibits polyglutamine aggregation and toxicity though induction of the heat shock response. J Mol Med 85:1421–1428. https://doi.org/10.1007/s00109-007-0251-9
Zhu X, Su B, Wang X et al (2007) Causes of oxidative stress in Alzheimer disease. Cell Mol Life Sci 64:2202–2210. https://doi.org/10.1007/s00018-007-7218-4
Zhu Z, Yan J, Jiang W et al (2013) Arctigenin effectively ameliorates memory impairment in Alzheimer’s disease model mice targeting both β-amyloid production and clearance. J Neurosci 33:13138–13149. https://doi.org/10.1523/JNEUROSCI.4790-12.2013
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This research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Fast-track Research Funding Program.
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This research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Fast-track Research Funding Program.
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Highlights
• Parkin, PINK1 are essential for PTMs and usually mutated in PD.
• CHIP, UCHL1, and TRAF6 have a role in the dysfunction of UPS in PD.
• Alternation the activity of GSK3β and PP2A have a role in progression of AD
• HDAC and EAAT2 are essential for PTMs and have a role in ALS.
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Elmatboly, A.M., Sherif, A.M., Deeb, D.A. et al. The impact of proteostasis dysfunction secondary to environmental and genetic causes on neurodegenerative diseases progression and potential therapeutic intervention. Environ Sci Pollut Res 27, 11461–11483 (2020). https://doi.org/10.1007/s11356-020-07914-1
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DOI: https://doi.org/10.1007/s11356-020-07914-1