Skip to main content
SpringerLink
Log in

Exploring the Role of Ubiquitin–Proteasome System in Parkinson's Disease

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Over the last decade, researchers have discovered that  a group of apparently unrelated neurodegenerative disorders, such as Parkinson's disease, have remarkable cellular and molecular biology similarities. Protein misfolding and aggregation are involved in all of the neurodegenerative conditions; as a result, inclusion bodies aggregation starts in the cells. Chaperone proteins and ubiquitin (26S proteasome's proteolysis signal), which aid in refolding misfolded proteins, are frequently found in these aggregates. The discovery of disease-causing gene alterations that code for multiple ubiquitin–proteasome pathway proteins in Parkinson's disease has strengthened the relationship between the ubiquitin–proteasome system and neurodegeneration. The specific molecular linkages between these systems and pathogenesis, on the other hand, are unknown and controversial. We outline the current level of knowledge in this article, focusing on important unanswered problems.

Graphical Abstract

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

Similar content being viewed by others

Data Availability

Not applicable.

Abbreviations

AA:

amino acid

AD:

Alzheimer's disease

ATG:

autophagy-related gene

CDCrel-1:

cell division control-related protein

CMA:

chaperone-mediated autophagy

CP:

core particle

E1:

ubiquitin-activating enzyme

E2:

ubiquitin-conjugating enzyme

E3:

ubiquitin-ligating enzyme

GstS1:

glutathione S-transferase S1

GABARAP:

g-aminobutyric acid receptor-associated protein

HSP 90:

heat shock protein 90

KO:

knock out

LC:

locus coeruleus

LC3:

microtubule-associated protein 1 light chain 3

Pael-R:

parkin-associated endothelial-like receptor

PD:

Parkinson's disease

PROTAC:

proteolysis targeting chimera

Sfp1:

split-finger protein 1

SnPc:

substantia nigra pars compacta

Ub:

ubiquitin

UCH-L1:

carboxyl-terminal hydrolase L1

UPS:

ubiquitin–proteasome system

References

  1. Wijeyekoon RS, Moore SF, Farrell K, Breen DP, Barker RA, Williams-Gray CH (2020) Cerebrospinal Fluid Cytokines and Neurodegeneration-Associated Proteins in Parkinson's Disease. Mov Disord 35:1062–1066. https://doi.org/10.1002/mds.28015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Nalls MA, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith IG, Chinnery PF, Morris CM, Theuns J, Crosiers D, Cras P, Engelborghs S (2013) A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA Neurol 70:727–735. https://doi.org/10.1001/jamaneurol.2013.1925

    Article  PubMed  Google Scholar 

  3. Guerreiro R, Escott-Price V, Darwent L, Parkkinen L, Ansorge O, Hernandez DG, Nalls MA, Clark L, Honig L, Marder K, van der Flier W (2016) Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases. Neurobiol Aging 38:214–2e7. https://doi.org/10.1016/j.neurobiolaging.2015.10.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Singh A, Dawson TM, Kulkarni S (2021) Neurodegenerative disorders and gut-brain interactions. J Clin Investig 131:e143775. https://doi.org/10.1172/JCI143775

    Article  CAS  Google Scholar 

  5. Kelleher RJ, Shen J (2017) Presenilin-1 mutations and Alzheimer’s disease. Proc Natl Acad Sci 114:629–631. https://doi.org/10.1073/pnas.1619574114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dawkins E, Small DH (2014) Insights into the physiological function of the β-amyloid precursor protein: beyond Alzheimer's disease. J Neurochem 129:756–769. https://doi.org/10.1111/jnc.12675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Saccon RA, Bunton-Stasyshyn RK, Fisher EM, Fratta P (2013) Is SOD1 loss of function involved in amyotrophic lateral sclerosis? Brain 136:2342–2358. https://doi.org/10.1093/brain/awt097

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sieradzan KA, Mechan AO, Jones L, Wanker EE, Nukina N, Mann DM (1999) Huntington's disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein. Exp Neurol 156:92–99. https://doi.org/10.1006/exnr.1998.7005

    Article  CAS  PubMed  Google Scholar 

  9. Scoles DR, Meera P, Schneider MD, Paul S, Dansithong W, Figueroa KP, Hung G, Rigo F, Bennett CF, Otis TS, Pulst SM (2017) Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Nature 544:362–366. https://doi.org/10.1038/nature22044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhu Q, Zhuang XX, Chen JY, Yuan NN, Chen Y, Cai CZ, Tan JQ, Su HX, Lu JH (2021) Lycorine, a natural alkaloid, promotes the degradation of alpha-synuclein via PKA-mediated UPS activation in transgenic Parkinson's disease models. Phytomedicine 87:153578. https://doi.org/10.1016/j.phymed.2021.153578

    Article  CAS  PubMed  Google Scholar 

  11. Ham SJ, Lee D, Xu WJ, Cho E, Choi S, Min S, Park S, Chung J (2021) Loss of UCHL1 rescues the defects related to Parkinson’s disease by suppressing glycolysis. Sci Adv 7:eabg4574. https://doi.org/10.1126/sciadv.abg4574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hirsch EC, Standaert DG (2021) Ten unsolved questions about neuroinflammation in Parkinson's disease. Mov Disord 36:16–24. https://doi.org/10.1002/mds.28075

    Article  PubMed  Google Scholar 

  13. Jiang P, Dickson DW (2018) Parkinson’s disease: experimental models and reality. Acta Neuropathol 135:13–32. https://doi.org/10.1007/s00401-017-1788-5

    Article  CAS  PubMed  Google Scholar 

  14. Mulder MP, Witting KF, Ovaa H (2019) Cracking the ubiquitin Code: the ubiquitin toolbox. Curr Issues Mol Biol 37:1–20. https://doi.org/10.21775/cimb.037.001

    Article  PubMed  Google Scholar 

  15. Cao Y, Zhu H, He R, Kong L, Shao J, Zhuang R, Xi J, Zhang J (2020) Proteasome, a promising therapeutic target for multiple diseases beyond cancer. Drug Des Devel Ther 14:4327. https://doi.org/10.2147/DDDT.S265793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kist M, Vucic D (2021) Cell death pathways: intricate connections and disease implications. EMBO J 40:e106700. https://doi.org/10.15252/embj.2020106700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Webster CP, Smith EF, Shaw PJ, De Vos KJ (2017) Protein homeostasis in amyotrophic lateral sclerosis: therapeutic opportunities? Front Mol Neurosci 10:123. https://doi.org/10.3389/fnmol.2017.00123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kalkan AC, Kahraman T, Ugut BO, Colakoglu BD, Genc A (2020) A comparison of the relationship between manual dexterity and postural control in young and older individuals with Parkinson’s disease. J Clin Neurosci 75:89–93. https://doi.org/10.1016/j.jocn.2020.03.018

    Article  PubMed  Google Scholar 

  19. Osellame LD, Duchen MR (2013) Defective quality control mechanisms and accumulation of damaged mitochondria link Gaucher and Parkinson diseases. Autophagy 9:1633–1635. https://doi.org/10.4161/auto.25878

    Article  CAS  PubMed  Google Scholar 

  20. Liddell JR, White AR (2018) Nexus between mitochondrial function, iron, copper and glutathione in Parkinson's disease. Neurochem Int 117:126–138. https://doi.org/10.1016/j.neuint.2017.05.016

    Article  CAS  PubMed  Google Scholar 

  21. Vila M, Laguna A, Carballo-Carbajal I (2019) Intracellular crowding by age-dependent neuromelanin accumulation disrupts neuronal proteostasis and triggers Parkinson disease pathology. Autophagy 15:2028–2030. https://doi.org/10.1080/15548627.2019.1659621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. McNaught KS, Perl DP, Brownell AL, Olanow CW (2004) Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease. Ann Neurol 56:149–162. https://doi.org/10.1002/ana.20186

    Article  CAS  PubMed  Google Scholar 

  23. Bové J, Zhou C, Jackson-Lewis V, Taylor J, Chu Y, Rideout HJ, Wu DC, Kordower JH, Petrucelli L, Przedborski S (2006) Proteasome inhibition and Parkinson's disease modeling. Ann Neurol 60:260–264. https://doi.org/10.1002/ana.20937

    Article  CAS  PubMed  Google Scholar 

  24. Zeng BY, Bukhatwa S, Hikima A, Rose S, Jenner P (2006) Reproducible nigral cell loss after systemic proteasomal inhibitor administration to rats. Ann Neurol 60:248–252. https://doi.org/10.1002/ana.20932

    Article  PubMed  Google Scholar 

  25. Bedford L, Hay D, Devoy A, Paine S, Powe DG, Seth R, Gray T, Topham I, Fone K, Rezvani N, Mee M (2008) Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies. J Neurosci 28:8189–8198. https://doi.org/10.1523/JNEUROSCI.2218-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kordower JH, Kanaan NM, Chu Y, Suresh Babu R, Stansell J III, Terpstra BT, Sortwell CE, Steece-Collier K, Collier TJ (2006) Failure of proteasome inhibitor administration to provide a model of Parkinson's disease in rats and monkeys. Ann Neurol 60:264–268. https://doi.org/10.1002/ana.20935

    Article  CAS  PubMed  Google Scholar 

  27. Jiang H, Yu Y, Liu S, Zhu M, Dong X, Wu J, Zhang Z, Zhang M, Zhang Y (2019) Proteomic study of a Parkinson's disease model of undifferentiated SH-SY5Y cells induced by a proteasome inhibitor. Int J Med Sci 16:84. https://doi.org/10.7150/ijms.28595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bentea E, Verbruggen L, Massie A (2017) The proteasome inhibition model of Parkinson’s disease. J Parkinsons Dis 7:31–63. https://doi.org/10.3233/JPD-160921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Greene ER, Dong KC, Martin A (2020) Understanding the 26S proteasome molecular machine from a structural and conformational dynamics perspective. Curr Opin Struct Biol 61:33–41. https://doi.org/10.1016/j.sbi.2019.10.004

    Article  CAS  PubMed  Google Scholar 

  30. Demasi M, da Cunha FM (2018) The physiological role of the free 20S proteasome in protein degradation: a critical review. BBA 1862:2948–2954. https://doi.org/10.1016/j.bbagen.2018.09.009

    Article  CAS  Google Scholar 

  31. Kommaddi RP, Shenoy SK (2013) Arrestins and protein ubiquitination. Prog Mol Biol Transl Sci 118:175–204. https://doi.org/10.1016/B978-0-12-394440-5.00007-3

    Article  CAS  PubMed  Google Scholar 

  32. Wang Y, Tang C, Wang E, Wang J (2014) PolyUbiquitin chain linkage topology selects the functions from the underlying binding landscape. PLoS Comput Biol 10:e1003691. https://doi.org/10.1371/journal.pcbi.1003691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Luza S, Opazo CM, Bousman CA, Pantelis C, Bush AI, Everall IP (2020) The ubiquitin proteasome system and schizophrenia. Lancet Psychiatry 7:528–537. https://doi.org/10.1016/S2215-0366(19)30520-6

    Article  PubMed  Google Scholar 

  34. Colberg L, Cammann C, Greinacher A, Seifert U (2020) Structure and function of the ubiquitin-proteasome system in platelets. J Thromb Haemost 18:771–780. https://doi.org/10.1111/jth.14730

    Article  CAS  PubMed  Google Scholar 

  35. Mao Y (2021) Structure, dynamics and function of the 26S proteasome. InMacromolecular Protein Complexes III: Structure and Function. Springer, Cham p. 1-151. https://doi.org/10.1007/978-3-030-58971-4_1

  36. Davis C, Spaller BL, Matouschek A (2021) Mechanisms of substrate recognition by the 26S proteasome. Curr Opin Struct 67:161–169. https://doi.org/10.1016/j.sbi.2020.10.010

    Article  CAS  Google Scholar 

  37. Butler EK, Voigt A, Lutz AK, Toegel JP, Gerhardt E, Karsten P, Falkenburger B, Reinartz A, Winklhofer KF, Schulz JB (2012) The mitochondrial chaperone protein TRAP1 mitigates α-Synuclein toxicity. PLoS Genet 8:e1002488. https://doi.org/10.1371/journal.pgen.1002488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Klucken J, Shin Y, Masliah E, Hyman BT, McLean PJ (2004) Hsp70 reduces α-synuclein aggregation and toxicity. J Biol Chem 279:25497–25502. https://doi.org/10.1074/jbc.M400255200

    Article  CAS  PubMed  Google Scholar 

  39. Wang XJ, Yu J, Wong SH, Cheng AS, Chan FK, Ng SS, Cho CH, Sung JJ, Wu WK (2013) A novel crosstalk between two major protein degradation systems: regulation of proteasomal activity by autophagy. Autophagy 9:1500–1508. https://doi.org/10.4161/auto.25573

    Article  CAS  PubMed  Google Scholar 

  40. Bao XQ, Kong XC, Qian C, Zhang D (2012) FLZ protects dopaminergic neuron through activating protein kinase B/mammalian target of rapamycin pathway and inhibiting RTP801 expression in Parkinson's disease models. Neuroscience 202:396–404. https://doi.org/10.1016/j.neuroscience.2011.11.036

    Article  CAS  PubMed  Google Scholar 

  41. Sakata E, Eisele MR, Baumeister W (2020) Molecular and cellular dynamics of the 26S proteasome. Biochim Biophys Acta, Proteins Proteomics 13:140583. https://doi.org/10.1016/j.bbapap.2020.140583

    Article  CAS  Google Scholar 

  42. Martinez-Fonts K, Davis C, Tomita T, Elsasser S, Nager AR, Shi Y, Finley D, Matouschek A (2020) The proteasome 19S cap and its ubiquitin receptors provide a versatile recognition platform for substrates. Nat Commun 11:1–6. https://doi.org/10.1038/s41467-019-13906-8

    Article  CAS  Google Scholar 

  43. Budenholzer L, Cheng CL, Li Y, Hochstrasser M (2017) Proteasome structure and assembly. J Mol Biol 429:3500–3524. https://doi.org/10.1016/j.jmb.2017.05.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Thibaudeau TA, Smith DM (2019) A practical review of proteasome pharmacology. Pharmacol Rev 71:170–197. https://doi.org/10.1124/pr.117.015370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bard JA, Goodall EA, Greene ER, Jonsson E, Dong KC, Martin A (2018) Structure and function of the 26S proteasome. Annu Rev Biochem 87:697–724. https://doi.org/10.1146/annurev-biochem-062917-011931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Shin JY, Muniyappan S, Tran NN, Park H, Lee SB, Lee BH (2020) Deubiquitination reactions on the proteasome for proteasome versatility. Int J Mol Sci 21:5312. https://doi.org/10.3390/ijms21155312

    Article  CAS  PubMed Central  Google Scholar 

  47. Highet B, Dieriks BV, Murray HC, Faull RL, Curtis MA (2020) Huntingtin Aggregates in the Olfactory Bulb in Huntington’s Disease. Front Aging Neurosci 12:261. https://doi.org/10.3389/fnagi.2020.00261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mogk A, Bukau B, Kampinga HH (2018) Cellular handling of protein aggregates by disaggregation machines. Mol Cell 69:214–226. https://doi.org/10.1016/j.molcel.2018.01.004

    Article  CAS  PubMed  Google Scholar 

  49. Makletsova MG, Syatkin SP, Poleshchuk VV, Urazgildeeva GR, Chigaleychik LA, Sungrapova CY, Illarioshkin SN (2019) Polyamines in Parkinson’s disease: their role in oxidative stress induction and protein aggregation. J Neurol Res 9:1–7. https://doi.org/10.14740/jnr509

    Article  Google Scholar 

  50. Kouli A, Torsney KM, Kuan WL (2018) Parkinson’s disease: etiology, neuropathology, and pathogenesis. Exon Publications 21:3–26. https://doi.org/10.15586/codonpublications.parkinsonsdisease.2018.ch1

    Article  Google Scholar 

  51. McCormack A, Keating DJ, Chegeni N, Colella A, Wang JJ, Chataway T (2019) Abundance of synaptic vesicle-related proteins in alpha-synuclein-containing protein inclusions suggests a targeted formation mechanism. Neurotox Res 35:883–897. https://doi.org/10.1007/s12640-019-00014-0

    Article  CAS  PubMed  Google Scholar 

  52. Matsumoto G, Inobe T, Amano T, Murai K, Nukina N, Mori N (2018) N-Acyldopamine induces aggresome formation without proteasome inhibition and enhances protein aggregation via p62/SQSTM1 expression. Sci Rep 8:1–4. https://doi.org/10.1038/s41598-018-27872-6

    Article  CAS  Google Scholar 

  53. Meyer HJ, Rape M (2014) Enhanced protein degradation by branched ubiquitin chains. Cell 157:910–921. https://doi.org/10.1016/j.cell.2014.03.037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Varshavsky A (2017) The ubiquitin system, autophagy, and regulated protein degradation. Annu Rev Biochem 86:123–128. https://doi.org/10.1146/annurev-biochem-061516-044859

    Article  CAS  PubMed  Google Scholar 

  55. Hrelia P, Sita G, Ziche M, Ristori E, Marino A, Cordaro M, Molteni R, Spero V, Malaguti M, Morroni F, Hrelia S (2020) Common protective strategies in neurodegenerative disease: focusing on risk factors to target the cellular redox system. Oxidative Med Cell Longev 2020. https://doi.org/10.1155/2020/8363245

  56. Upadhyay A, Sundaria N, Dhiman R, Prajapati VK, Prasad A, Mishra A (2021) Complex Inclusion Bodies and Defective Proteome Hubs in Neurodegenerative Disease: New Clues, New Challenges. Neuroscientist 3:1073858421989582. https://doi.org/10.1177/1073858421989582

    Article  Google Scholar 

  57. Appel-Cresswell S, Vilarino-Guell C, Encarnacion M, Sherman H, Yu I, Shah B, Weir D, Thompson C, Szu-Tu C, Trinh J, Aasly JO (2013) Alpha-synuclein p. H50Q, a novel pathogenic mutation for Parkinson's disease. Mov Disord 28:811–813. https://doi.org/10.1002/mds.25421

    Article  CAS  PubMed  Google Scholar 

  58. Chen H, Huang X, Yuan L, Xia H, Xu H, Yang Y, Zheng W, Deng H (2016) A homozygous parkin p. G284R mutation in a Chinese family with autosomal recessive juvenile parkinsonism. Neurosci Lett 624:100–104. https://doi.org/10.1016/j.neulet.2016.05.011

    Article  CAS  PubMed  Google Scholar 

  59. Taipa R, Pereira C, Reis I, Alonso I, Bastos-Lima A, Melo-Pires M, Magalhaes M (2016) DJ-1 linked parkinsonism (PARK7) is associated with Lewy body pathology. Brain 139:1680–1687. https://doi.org/10.1093/brain/aww080

    Article  PubMed  Google Scholar 

  60. Bellomo G, Paciotti S, Gatticchi L, Parnetti L (2020) The vicious cycle between α-synuclein aggregation and autophagic-lysosomal dysfunction. Mov Disord 35:34–44. https://doi.org/10.1002/mds.27895

    Article  CAS  PubMed  Google Scholar 

  61. Ristic G, Tsou WL, Todi SV (2014) An optimal ubiquitin-proteasome pathway in the nervous system: the role of deubiquitinating enzymes. Front Mol Neurosci 7:72. https://doi.org/10.3389/fnmol.2014.00072

    Article  PubMed  PubMed Central  Google Scholar 

  62. Wahl C, Kautzmann S, Krebiehl G, Strauss K, Woitalla D, Müller T, Bauer P, Riess O, Krüger R (2008) A comprehensive genetic study of the proteasomal subunit S6 ATPase in German Parkinson’s disease patients. J Neural Transm 115:1141. https://doi.org/10.1007/s00702-008-0054-3

    Article  CAS  PubMed  Google Scholar 

  63. Paine SM, Anderson G, Bedford K, Lawler K, Mayer RJ, Lowe J, Bedford L (2013) Pale body-like inclusion formation and neurodegeneration following depletion of 26S proteasomes in mouse brain neurones are independent of α-synuclein. PLoS One 8:e54711. https://doi.org/10.1371/journal.pone.0054711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Tofaris GK, Layfield R, Spillantini MG (2001) α-Synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Lett 509:22–26. https://doi.org/10.1016/S0014-5793(01)03115-5

    Article  CAS  PubMed  Google Scholar 

  65. Inamdar NN, Arulmozhi DK, Tandon A, Bodhankar SL (2007) Parkinson's disease: genetics and beyond. Curr Neuropharmacol 5:99–113. https://doi.org/10.2174/157015907780866893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Rao G, Croft B, Teng C, Awasthi V (2015) Ubiquitin-Proteasome System in Neurodegenerative Disorders. J Drug Metab Toxicol 2:1–6. https://doi.org/10.4172/2157-7609.1000187

    Article  CAS  Google Scholar 

  67. Bentea E, Van der Perren A, Van Liefferinge J, El Arfani A, Albertini G, Demuyser T, Merckx E, Michotte Y, Smolders I, Baekelandt V, Massie A (2015) Nigral proteasome inhibition in mice leads to motor and non-motor deficits and increased expression of Ser129 phosphorylated α-synuclein. Front Behav Neurosci 9:68. https://doi.org/10.3389/fnbeh.2015.00068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. de Vries RL, Przedborski S (2013) Mitophagy and Parkinson's disease: be eaten to stay healthy. Mol Cell Neurosci 55:37–43. https://doi.org/10.1016/j.mcn.2012.07.008

    Article  CAS  PubMed  Google Scholar 

  69. Klein C, Lohmann-Hedrich K (2007) Impact of recent genetic findings in Parkinson's disease. Curr Opin Neurol 20:453–464. https://doi.org/10.1097/WCO.0b013e3281e6692b

    Article  CAS  PubMed  Google Scholar 

  70. Leinartaité L, Svenningsson P (2017) Folding underlies bidirectional role of GPR37/Pael-R in Parkinson disease. Trends Pharmacol Sci 38:749–760. https://doi.org/10.1016/j.tips.2017.05.006

    Article  CAS  PubMed  Google Scholar 

  71. Tang MY, Vranas M, Krahn AI, Pundlik S, Trempe JF, Fon EA (2017) Structure-guided mutagenesis reveals a hierarchical mechanism of Parkin activation. Nat Commun 8:1–4. https://doi.org/10.1038/ncomms14697

    Article  Google Scholar 

  72. Dove KK, Klevit RE, Rittinger K (2015) pUBLically unzipping Parkin: how phosphorylation exposes a ligase bit by bit. EMBO J 34:2486–2488. https://doi.org/10.15252/embj.201592857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein MJ, Jonnalagada S, Chernova T, Dehejia A (1998) The ubiquitin pathway in Parkinson's disease. Nature 395:451–452. https://doi.org/10.1038/26652

    Article  CAS  PubMed  Google Scholar 

  74. Maraganore DM, Farrer MJ, Hardy JA, Lincoln SJ, McDonnell SK, Rocca WA (1999) Case-control study of the ubiquitin carboxy-terminal hydrolase L1 gene in Parkinson’s disease. Neurology 1:1858. https://doi.org/10.1212/WNL.53.8.1858

    Article  Google Scholar 

  75. Sun F, Kanthasamy A, Anantharam V, Kanthasamy AG (2007) Environmental neurotoxic chemicals-induced ubiquitin proteasome system dysfunction in the pathogenesis and progression of Parkinson's disease. Pharmacol Ther 114:327–344. https://doi.org/10.1016/j.pharmthera.2007.04.001

    Article  CAS  PubMed  Google Scholar 

  76. Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, Wacker M, Klose J, Shen J (2004) Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 279:18614–18622. https://doi.org/10.1074/jbc.M401135200

    Article  CAS  PubMed  Google Scholar 

  77. Snyder NA, Silva GM (2021) Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response. J Biol Chem 297:101077. https://doi.org/10.1016/j.jbc.2021.101077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Matsuda N, Tanaka K (2010) Does impairment of the ubiquitin-proteasome system or the autophagy-lysosome pathway predispose individuals to neurodegenerative disorders such as Parkinson's disease? J Alzheimers Dis 19:1–9. https://doi.org/10.3233/JAD-2010-1231

    Article  CAS  PubMed  Google Scholar 

  79. Maraganore DM, Lesnick TG, Elbaz A, Chartier-Harlin MC, Gasser T, Krüger R, Hattori N, Mellick GD, Quattrone A, Satoh JI, Toda T (2004) UCHL1 is a Parkinson's disease susceptibility gene. Ann Neurol 55:512–521. https://doi.org/10.1002/ana.20017

    Article  CAS  PubMed  Google Scholar 

  80. Healy DG, Abou-Sleiman PM, Casas JP, Ahmadi KR, Lynch T, Gandhi S, Muqit MM, Foltynie T, Barker R, Bhatia KP, Quinn NP (2006) UCHL-1 is not a Parkinson's disease susceptibility gene. Ann Neurol 59:627–633. https://doi.org/10.1002/ana.20757

    Article  CAS  PubMed  Google Scholar 

  81. Bishop P, Rocca D, Henley JM (2016) Ubiquitin C-terminal hydrolase L1 (UCH-L1): structure, distribution and roles in brain function and dysfunction. Biochem J 473:2453–2462. https://doi.org/10.1042/BCJ20160082

    Article  CAS  PubMed  Google Scholar 

  82. Wang KK, Yang Z, Sarkis G, Torres I, Raghavan V (2017) Ubiquitin C-terminal hydrolase-L1 (UCH-L1) as a therapeutic and diagnostic target in neurodegeneration, neurotrauma and neuro-injuries. Expert Opin Ther Targets 21:627–638. https://doi.org/10.1080/14728222.2017.1321635

    Article  CAS  PubMed  Google Scholar 

  83. Andersson FI, Werrell EF, McMorran L, Crone WJ, Das C, Hsu ST, Jackson SE (2011) The effect of Parkinson's-disease-associated mutations on the deubiquitinating enzyme UCH-L1. J Mol Biol 407:261–272. https://doi.org/10.1016/j.jmb.2010.12.029

    Article  CAS  PubMed  Google Scholar 

  84. Bose A, Beal MF (2016) Mitochondrial dysfunction in Parkinson's disease. J Neurochem 139:216–231. https://doi.org/10.1111/jnc.13731

    Article  CAS  PubMed  Google Scholar 

  85. Ono K, Ikeda T, Takasaki JI, Yamada M (2011) Familial Parkinson disease mutations influence α-synuclein assembly. Neurobiol Dis 43:715–724. https://doi.org/10.1016/j.nbd.2011.05.025

    Article  CAS  PubMed  Google Scholar 

  86. Sun F, Anantharam V, Latchoumycandane C, Kanthasamy A, Kanthasamy AG (2005) Dieldrin induces ubiquitin-proteasome dysfunction in α-synuclein overexpressing dopaminergic neuronal cells and enhances susceptibility to apoptotic cell death. J Pharmacol Exp Ther 315:69–79. https://doi.org/10.1124/jpet.105.084632

    Article  CAS  PubMed  Google Scholar 

  87. Maries E, Dass B, Collier TJ, Kordower JH, Steece-Collier K (2003) The role of α-synuclein in Parkinson's disease: insights from animal models. Nat Rev Neurosci 4:727–738. https://doi.org/10.1038/nrn1199

    Article  CAS  PubMed  Google Scholar 

  88. Dehay B, Vila M, Bezard E, Brundin P, Kordower JH (2016) Alpha-synuclein propagation: new insights from animal models. Mov Disord 31:161–168. https://doi.org/10.1002/mds.26370

    Article  PubMed  Google Scholar 

  89. Cummins N, Tweedie A, Zuryn S, Bertran-Gonzalez J, Götz J (2019) Disease-associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria. EMBO J 38:e99360. https://doi.org/10.15252/embj.201899360

    Article  CAS  PubMed  Google Scholar 

  90. Perez FA, Palmiter RD (2005) Parkin-deficient mice are not a robust model of parkinsonism. Proc Natl Acad Sci 102:2174–2179. https://doi.org/10.1073/pnas.0409598102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. und Halbach OV, Schober A, Krieglstein K (2004) Genes, proteins, and neurotoxins involved in Parkinson’s disease. Prog Neurobiol 73:151-177. https://doi.org/10.1016/j.pneurobio.2004.05.002

  92. Berko D, Herkon O, Braunstein I, Isakov E, David Y, Ziv T, Navon A, Stanhill A (2014) Inherent asymmetry in the 26S proteasome is defined by the ubiquitin receptor RPN13. J Biol Chem 289:5609–5618. https://doi.org/10.1074/jbc.M113.509380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Alexopoulou Z, Lang J, Perrett RM, Elschami M, Hurry ME, Kim HT, Mazaraki D, Szabo A, Kessler BM, Goldberg AL, Ansorge O (2016) Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease. Proc Natl Acad Sci 113:E4688–E4697. https://doi.org/10.1073/pnas.1523597113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zucchelli S, Codrich M, Marcuzzi F, Pinto M, Vilotti S, Biagioli M, Ferrer I, Gustincich S (2010) TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains. Hum Mol Genet 19:3759–3770. https://doi.org/10.1093/hmg/ddq290

    Article  CAS  PubMed  Google Scholar 

  95. Wakabayashi K, Tanji K, Odagiri S, Miki Y, Mori F, Takahashi H (2013) The Lewy body in Parkinson’s disease and related neurodegenerative disorders. Mol Neurobiol 47:495–508. https://doi.org/10.1007/s12035-012-8280-y

    Article  CAS  PubMed  Google Scholar 

  96. Franco-Iborra S, Vila M, Perier C (2018) Mitochondrial quality control in neurodegenerative diseases: focus on Parkinson's disease and Huntington's disease. Front Neurosci 12:342. https://doi.org/10.3389/fnins.2018.00342

    Article  PubMed  PubMed Central  Google Scholar 

  97. Shin WH, Park JH, Chung KC (2020) The central regulator p62 between ubiquitin proteasome system and autophagy and its role in the mitophagy and Parkinson’s disease. BMB Rep 53:56. https://doi.org/10.5483/BMBRep.2020.53.1.283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Sugatani J, Noguchi Y, Hattori Y, Yamaguchi M, Yamazaki Y, Ikari A (2016) Threonine-408 regulates the stability of human pregnane X receptor through its phosphorylation and the CHIP/chaperone-autophagy pathway. Drug Metab Dispos 44:137–150. https://doi.org/10.1124/dmd.115.066308

    Article  CAS  PubMed  Google Scholar 

  99. El-Saiy KA, Sayed RH, El-Sahar AE, Kandil EA (2022) Modulation of histone deacetylase, the ubiquitin proteasome system, and autophagy underlies the neuroprotective effects of venlafaxine in a rotenone-induced Parkinson's disease model in rats. Chem Biol Interact 354:109841. https://doi.org/10.1016/j.cbi.2022.109841

    Article  CAS  PubMed  Google Scholar 

  100. Wang XL, Feng ST, Wang YT, Yuan YH, Li ZP, Chen NH, Wang ZZ, Zhang Y (2021) Mitophagy, a Form of Selective Autophagy, Plays an Essential Role in Mitochondrial Dynamics of Parkinson’s Disease. Cell Mol Neurobiol 2021:1–9. https://doi.org/10.1007/s10571-021-01039-w

    Article  CAS  Google Scholar 

  101. Khaminets A, Behl C, Dikic I (2016) Ubiquitin-dependent and independent signals in selective autophagy. Trends Cell Biol 26(1):6–16. https://doi.org/10.1016/j.tcb.2015.08.010

    Article  CAS  PubMed  Google Scholar 

  102. Huang CY, Sivalingam K, Shibu MA, Liao PH, Ho TJ, Kuo WW, Chen RJ, Day CH, Viswanadha VP, Ju DT (2020) Induction of autophagy by vasicinone protects neural cells from mitochondrial dysfunction and attenuates paraquat-mediated Parkinson’s disease associated α-synuclein levels. Nutrients 12:1707. https://doi.org/10.3390/nu12061707

    Article  CAS  PubMed Central  Google Scholar 

  103. Shen YF, Tang Y, Zhang XJ, HuANG KX, Le WD (2013) Adaptive changes in autophagy after UPS impairment in Parkinson's disease. Acta Pharmacol Sin 34(5):667–673. https://doi.org/10.1038/aps.2012.203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Rango M, Bresolin N (2018) Brain mitochondria, aging, and Parkinson’s disease. Genes 9:250. https://doi.org/10.3390/genes9050250

    Article  CAS  PubMed Central  Google Scholar 

  105. Cheng J, Deng Y, Zhou J (2021) Role of the Ubiquitin System in Chronic Pain. Front Mol Neurosci 14:674914. https://doi.org/10.3389/fnmol.2021.674914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Ross CA, Pickart CM (2004) The ubiquitin–proteasome pathway in Parkinson's disease and other neurodegenerative diseases. Trends Cell Biol 14:703–711. https://doi.org/10.1016/j.tcb.2004.10.006

    Article  CAS  PubMed  Google Scholar 

  107. Gupta N (2014) Ubiquitin-proteasome system modulates platelet function, Cleveland State University https://engagedscholarship.csuohio.edu/etdarchive/115

  108. Olanow CW, McNaught KS (2006) Ubiquitin–proteasome system and Parkinson's disease. Mov Disord 21:1806–1823. https://doi.org/10.1002/mds.21013

    Article  PubMed  Google Scholar 

  109. Moskal N, Riccio V, Bashkurov M, Taddese R, Datti A, Lewis PN, McQuibban GA (2020) ROCK inhibitors upregulate the neuroprotective Parkin-mediated mitophagy pathway. Nat Commun 11:1–4. https://doi.org/10.1038/s41467-019-13781-3

    Article  CAS  Google Scholar 

  110. Ge P, Dawson VL, Dawson TM (2020) PINK1 and Parkin mitochondrial quality control: A source of regional vulnerability in Parkinson’s disease. Mol Neurodegener 15:1–8. https://doi.org/10.1186/s13024-020-00367-7

    Article  Google Scholar 

  111. Kwak MK, Wakabayashi N, Greenlaw JL, Yamamoto M, Kensler TW (2003) Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol Cell Biol 23:8786–8794. https://doi.org/10.1128/MCB.23.23.8786-8794.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Crider A, Pandya CD, Peter D, Ahmed AO, Pillai A (2014) Ubiquitin-proteasome dependent degradation of GABA A α1 in autism spectrum disorder. Mol Autism 5:1-0. https://doi.org/10.1186/2040-2392-5-45

  113. Bareggi SR, Cornelli U (2012) Clioquinol: review of its mechanisms of action and clinical uses in neurodegenerative disorders. CNS Neurosci Ther 18:41–46. https://doi.org/10.1111/j.1755-5949.2010.00231.x

    Article  CAS  PubMed  Google Scholar 

  114. Stefanova N, Kaufmann WA, Humpel C, Poewe W, Wenning GK (2012) Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. Acta Neuropathol 124:51–65. https://doi.org/10.1007/s00401-012-0977-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Ma Y, Xu B, Fang Y, Yang Z, Cui J, Zhang L, Zhang L (2011) Synthesis and SAR study of novel peptide aldehydes as inhibitors of 20S proteasome. Molecules 16:7551–7564. https://doi.org/10.3390/molecules16097551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Bir A, Sen O, Anand S, Khemka VK, Banerjee P, Cappai R, Sahoo A, Chakrabarti S (2014) α-synuclein-induced mitochondrial dysfunction in isolated preparation and intact cells: Implications in the pathogenesis of Parkinson's disease. J Neurochem 131:868–877. https://doi.org/10.1111/jnc.12966

    Article  CAS  PubMed  Google Scholar 

  117. Zhou Z, Kerk S, Meng Lim T (2008) Endogenous dopamine (DA) renders dopaminergic cells vulnerable to challenge of proteasome inhibitor MG132. Free Radic Res 42:456–466. https://doi.org/10.1080/10715760802005177

    Article  CAS  PubMed  Google Scholar 

  118. Jung EB, Lee CS (2014) Baicalein attenuates proteasome inhibition-induced apoptosis by suppressing the activation of the mitochondrial pathway and the caspase-8-and Bid-dependent pathways. Eur J Pharmacol 730:116–124. https://doi.org/10.1016/j.ejphar.2014.02.039

    Article  CAS  PubMed  Google Scholar 

  119. Hegde AN, Haynes KA, Bach SV, Beckelman BC (2014) Local ubiquitin-proteasome-mediated proteolysis and long-term synaptic plasticity. Front Mol Neurosci 7:96. https://doi.org/10.3389/fnmol.2014.00096

    Article  PubMed  PubMed Central  Google Scholar 

  120. Snider BJ, Tee LY, Canzoniero LM, Babcock DJ, Choi DW (2002) NMDA antagonists exacerbate neuronal death caused by proteasome inhibition in cultured cortical and striatal neurons. Eur J Neurosci 15:419–428. https://doi.org/10.1046/j.0953-816x.2001.01867.x

    Article  PubMed  Google Scholar 

  121. Höglinger GU, Carrard G, Michel PP, Medja F, Lombès A, Ruberg M, Friguet B, Hirsch EC (2003) Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson's disease. J Neurochem 86:1297–1307. https://doi.org/10.1046/j.1471-4159.2003.01952.x

    Article  CAS  PubMed  Google Scholar 

  122. Chang KH, Lee-Chen GJ, Wu YR, Chen YJ, Lin JL, Li M, Chen IC, Lo YS, Wu HC, Chen CM (2016) Impairment of proteasome and anti-oxidative pathways in the induced pluripotent stem cell model for sporadic Parkinson's disease. Parkinsonism Relat Disord 24:81–88. https://doi.org/10.1016/j.parkreldis.2016.01.001

    Article  PubMed  Google Scholar 

  123. Filatova EV, Shadrina MI, Alieva AK, Kolacheva AA, Slominsky PA, Ugrumov MV (2014) Expression analysis of genes of ubiquitin-proteasome protein degradation system in MPTP-induced mice models of early stages of Parkinson’s disease. Dokl Biochem Biophys 116-118. https://doi.org/10.1134/S1607672914030107

  124. Whitworth AJ, Theodore DA, Greene JC, Beneš H, Wes PD, Pallanck LJ (2005) Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease. Proc Natl Acad Sci 102:8024–8029. https://doi.org/10.1073/pnas.0501078102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Madsen DA, Schmidt SI, Blaabjerg M, Meyer M (2021) Interaction between Parkin and α-Synuclein in PARK2-Mediated Parkinson’s Disease. Cells 10:283. https://doi.org/10.3390/cells10020283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Fabbri M, Perez-Lloret S, Rascol O (2020) Therapeutic strategies for Parkinson’s disease: promising agents in early clinical development. Expert Opin Investig Drugs 29:1249–1267. https://doi.org/10.1080/13543784.2020.1814252

    Article  CAS  PubMed  Google Scholar 

  127. Akhtar J, Wang Z, Zhang ZP, Bi MM (2013) Lentiviral-mediated RNA interference targeting stathmin1 gene in human gastric cancer cells inhibits proliferation in vitro and tumor growth in vivo. J Transl Med 11:1–9. https://doi.org/10.1186/1479-5876-11-212

    Article  CAS  Google Scholar 

  128. Shen HY, He JC, Wang Y, Huang QY, Chen JF (2005) Geldanamycin induces heat shock protein 70 and protects against MPTP-induced dopaminergic neurotoxicity in mice. J Biol Chem 280:39962–39969. https://doi.org/10.1074/jbc.M505524200

    Article  CAS  PubMed  Google Scholar 

  129. Opattova A, Cente M, Novak M, Filipcik P (2015) The ubiquitin proteasome system as a potential therapeutic target for treatment of neurodegenerative diseases. Gen Physiol Biophys 34:337–352. https://doi.org/10.4149/gpb_2015024

    Article  CAS  PubMed  Google Scholar 

  130. Dantuma NP, Bott LC (2014) The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution. Front Mol Neurosci 7:70. https://doi.org/10.3389/fnmol.2014.00070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Jeon J, Kim W, Jang J, Isacson O, Seo H (2016) Gene therapy by proteasome activator, PA28γ, improves motor coordination and proteasome function in Huntington’s disease YAC128 mice. Neuroscience 324:20–28. https://doi.org/10.1016/j.neuroscience.2016.02.054

    Article  CAS  PubMed  Google Scholar 

  132. Jung T, Grune T (2013) The proteasome and the degradation of oxidized proteins: part I—structure of proteasomes. Redox boil 1:178–182. https://doi.org/10.1016/j.redox.2013.01.004

    Article  CAS  Google Scholar 

  133. Lehrbach NJ, Breen PC, Ruvkun G (2019) Protein sequence editing of SKN-1A/Nrf1 by peptide: N-glycanase controls proteasome gene expression. Cell 177:737–750. https://doi.org/10.1016/j.cell.2019.03.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Vilchez D, Morantte I, Liu Z, Douglas PM, Merkwirth C, Rodrigues AP, Manning G, Dillin A (2012) RPN-6 determines C. elegans longevity under proteotoxic stress conditions. Nature 489:263–268. https://doi.org/10.1038/nature11315

    Article  CAS  PubMed  Google Scholar 

  135. Raina K, Crews CM (2017) Targeted protein knockdown using small molecule degraders. Curr Opin Chem Biol 39:46–53. https://doi.org/10.1016/j.cbpa.2017.05.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Schneekloth AR, Pucheault M, Tae HS, Crews CM (2008) Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics. Bioorg Med Chem Lett 18:5904–5908. https://doi.org/10.1016/j.bmcl.2008.07.114

    Article  CAS  PubMed  Google Scholar 

  137. Bondeson DP, Smith BE, Burslem GM, Buhimschi AD, Hines J, Jaime-Figueroa S, Wang J, Hamman BD, Ishchenko A, Crews CM (2018) Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem Biol 25:78–87. https://doi.org/10.1016/j.chembiol.2017.09.010

    Article  CAS  PubMed  Google Scholar 

  138. Lucas X, Ciulli A (2017) Recognition of substrate degrons by E3 ubiquitin ligases and modulation by small-molecule mimicry strategies. Curr Opin Struct Biol 44:101–110. https://doi.org/10.1016/j.sbi.2016.12.015

    Article  CAS  PubMed  Google Scholar 

  139. Au YZ, Wang T, Sigua LH, Qi J (2020) Peptide-based PROTAC: the predator of pathological proteins. Cell Chem Biol 27:637–639. https://doi.org/10.1016/j.chembiol.2020.06.002

    Article  CAS  PubMed  Google Scholar 

  140. Konstantinidou M, Oun A, Pathak P, Zhang B, Wang Z, Ter Brake F, Dolga AM, Kortholt A, Dömling A (2021) The tale of proteolysis targeting chimeras (PROTACs) for Leucine-Rich Repeat Kinase 2 (LRRK2). ChemMedChem 16:959. https://doi.org/10.1002/cmdc.202000872

    Article  CAS  PubMed  Google Scholar 

  141. Silva MC, Ferguson FM, Cai Q, Donovan KA, Nandi G, Patnaik D, Zhang T, Huang HT, Lucente DE, Dickerson BC, Mitchison TJ (2019) Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models. Elife 8:e45457. https://doi.org/10.7554/eLife.45457

    Article  PubMed  PubMed Central  Google Scholar 

  142. Smith MH, Ploegh HL, Weissman JS (2011) Road to ruin: targeting proteins for degradation in the endoplasmic reticulum. Science 334:1086–1090. https://doi.org/10.1126/science.1209235

    Article  CAS  PubMed  Google Scholar 

  143. Ohtake F, Baba A, Takada I, Okada M, Iwasaki K, Miki H, Takahashi S, Kouzmenko A, Nohara K, Chiba T, Fujii-Kuriyama Y (2007) Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. Nature 446:562–566. https://doi.org/10.1038/nature05683

    Article  CAS  PubMed  Google Scholar 

  144. Kawajiri K, Kobayashi Y, Ohtake F, Ikuta T, Matsushima Y, Mimura J, Pettersson S, Pollenz RS, Sakaki T, Hirokawa T, Akiyama T (2009) Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in ApcMin/+ mice with natural ligands. Proc Natl Acad Sci 106:13481–13486. https://doi.org/10.1073/pnas.0902132106

    Article  PubMed  PubMed Central  Google Scholar 

  145. Luecke-Johansson S, Gralla M, Rundqvist H, Ho JC, Johnson RS, Gradin K, Poellinger L (2017) A molecular mechanism to switch the aryl hydrocarbon receptor from a transcription factor to an E3 ubiquitin ligase. Mol Cell Biol 37:e00630–e00616. https://doi.org/10.1128/MCB.00630-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Rana R, Coulter S, Kinyamu H, Goldstein JA (2013) RBCK1, an E3 ubiquitin ligase, interacts with and ubiquinates the human pregnane X receptor. Drug Metab Dispos 41:398–405. https://doi.org/10.1124/dmd.112.048728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgment

The authors would like to thank Chitkara College of Pharmacy, Chitkara University, Punjab, India, for providing the various resources for completion of the current article.

Funding

The current article did not receive any funding.

Author information

Authors and Affiliations

  1. Chitkara College of Pharmacy, Chitkara University, Punjab, India

    Tapan Behl, Sachin Kumar, Aayush Sehgal, Sukhbir Singh, Neelam Sharma & Vishnu Nayak Badavath

  2. Department of Medical Laboratories Sciences, College of Applied Medical Sciences in Alquwayiyah, Shaqra University, Riyadh, Saudi Arabia

    Ziyad M. Althafar

  3. Yashraj Institute of Pharmacy, Uttar Pradesh, India

    Shivam Yadav

  4. Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, Oman

    Saurabh Bhatia & Ahmed Al-Harrasi

  5. School of Health Science, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India

    Saurabh Bhatia

  6. Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan, Saudi Arabia

    Yosif Almoshari

  7. Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Madinah, Saudi Arabia

    Mohannad A. Almikhlafi

  8. Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania

    Simona Bungau

Authors
  1. Tapan Behl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sachin Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ziyad M. Althafar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aayush Sehgal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sukhbir Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Neelam Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vishnu Nayak Badavath
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shivam Yadav
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Saurabh Bhatia
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ahmed Al-Harrasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yosif Almoshari
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mohannad A. Almikhlafi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Simona Bungau
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TB and SK conceived the idea and wrote the first draft; ZMA, SS, NS and VNB reviewed the literature; AS and SY worked on figures; SB, AAH, and YA edited the manuscript; TB, MAA, and SBU did proof reading.

Corresponding author

Correspondence to Tapan Behl.

Ethics declarations

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent to Publish

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

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

Highlights

• In the aetiology of Parkinson's disease, the vicious cycle between proteasome failure and protein accumulation is crucial.

• The ubiquitin–proteasome system (UPS) is the primary hydrolytic system involved in the bulk of protein breakdown.

• PROTAC's development brings up new possibilities for treating Parkinson's disease through proteasome modulation.

• Proteasome homoeostasis regulation is a promising treatment for Parkinson's disease.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Behl, T., Kumar, S., Althafar, Z.M. et al. Exploring the Role of Ubiquitin–Proteasome System in Parkinson's Disease. Mol Neurobiol 59, 4257–4273 (2022). https://doi.org/10.1007/s12035-022-02851-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-022-02851-1

Keywords

Search

Navigation