Proteasome Inhibition Induces α-synuclein SUMOylation and Aggregate Formation

Overview

Journal J Neurol Sci

Publisher Elsevier

Specialty Neurology

Date 2011 Jun 7

PMID 21641618

Citations 49

Authors

Yong Man Kim

Won Hee Jang

Martha M Quezado

Yohan Oh

Kwang Chul Chung

Eunsung Junn

M Maral Mouradian

Affiliations

Soon will be listed here.

Abstract

Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are characterized pathologically by intraneuronal inclusions called Lewy bodies (LBs) and Lewy neurites. A major component of these inclusions is the protein α-synuclein, which is natively unfolded but forms oligomers and insoluble fibrillar aggregates under pathological conditions. Although α-synuclein is known to undergo several posttranslational modifications, the contribution of SUMOylation to α-synuclein aggregation and the pathogenesis of α-synucleinopathies have not been elucidated. Here, we provide evidence that aggregates and inclusions formed as a result of impaired proteasome activity contain SUMOylated α-synuclein. Additionally, SUMO1 is present in the halo of LBs colocalizing with α-synuclein in the brains of PD and DLB patients. Interestingly, SUMOylation does not affect the ubiquitination of α-synuclein. These findings suggest that proteasomal dysfunction results in the accumulation of SUMOylated α-synuclein and subsequently its aggregation, pointing to the contribution of this posttranslational modification to the pathogenesis of inclusion formation in α-synucleinopathies.

Citing Articles

Posttranslational Modifications of -Synuclein, Their Therapeutic Potential, and Crosstalk in Health and Neurodegenerative Diseases.

Hassanzadeh K, Liu J, Maddila S, Mouradian M Pharmacol Rev. 2024; 76(6):1254-1290.

PMID: 39164116 PMC: 11549938. DOI: 10.1124/pharmrev.123.001111.

Protein modification in neurodegenerative diseases.

Ramazi S, Dadzadi M, Darvazi M, Seddigh N, Allahverdi A MedComm (2020). 2024; 5(8):e674.

PMID: 39105197 PMC: 11298556. DOI: 10.1002/mco2.674.

Therapeutic Implications and Regulations of Protein Post-translational Modifications in Parkinsons Disease.

Mishra T, Singh S, Singh T Cell Mol Neurobiol. 2024; 44(1):53.

PMID: 38960968 PMC: 11222187. DOI: 10.1007/s10571-024-01471-8.

Paralogue-Specific Roles of SUMO1 and SUMO2/3 in Protein Quality Control and Associated Diseases.

Wang W, Matunis M Cells. 2024; 13(1).

PMID: 38201212 PMC: 10778024. DOI: 10.3390/cells13010008.

Epigenetic modification in Parkinson's disease.

Song H, Chen J, Huang J, Sun P, Liu Y, Xu L Front Cell Dev Biol. 2023; 11:1123621.

PMID: 37351278 PMC: 10283008. DOI: 10.3389/fcell.2023.1123621.

References

Tofaris G, Layfield R, Spillantini M . alpha-synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Lett. 2001; 509(1):22-6. DOI: 10.1016/s0014-5793(01)03115-5. View

Spillantini M, Schmidt M, Lee V, Trojanowski J, Jakes R, Goedert M . Alpha-synuclein in Lewy bodies. Nature. 1997; 388(6645):839-40. DOI: 10.1038/42166. View

Mahajan R, Gerace L, Melchior F . Molecular characterization of the SUMO-1 modification of RanGAP1 and its role in nuclear envelope association. J Cell Biol. 1998; 140(2):259-70. PMC: 2132567. DOI: 10.1083/jcb.140.2.259. View

Johnson E, Schwienhorst I, Dohmen R, Blobel G . The ubiquitin-like protein Smt3p is activated for conjugation to other proteins by an Aos1p/Uba2p heterodimer. EMBO J. 1997; 16(18):5509-19. PMC: 1170183. DOI: 10.1093/emboj/16.18.5509. View

Hodara R, Norris E, Giasson B, Mishizen-Eberz A, Lynch D, Lee V . Functional consequences of alpha-synuclein tyrosine nitration: diminished binding to lipid vesicles and increased fibril formation. J Biol Chem. 2004; 279(46):47746-53. DOI: 10.1074/jbc.M408906200. View

Zhang Y, Sarge K . Sumoylation of amyloid precursor protein negatively regulates Abeta aggregate levels. Biochem Biophys Res Commun. 2008; 374(4):673-8. PMC: 2596940. DOI: 10.1016/j.bbrc.2008.07.109. View

McNaught K, Belizaire R, Isacson O, Jenner P, Olanow C . Altered proteasomal function in sporadic Parkinson's disease. Exp Neurol. 2002; 179(1):38-46. DOI: 10.1006/exnr.2002.8050. View

Snyder H, Mensah K, Theisler C, Lee J, Matouschek A, Wolozin B . Aggregated and monomeric alpha-synuclein bind to the S6' proteasomal protein and inhibit proteasomal function. J Biol Chem. 2003; 278(14):11753-9. DOI: 10.1074/jbc.M208641200. View

Wilkinson K, Nakamura Y, Henley J . Targets and consequences of protein SUMOylation in neurons. Brain Res Rev. 2010; 64(1):195-212. PMC: 3310160. DOI: 10.1016/j.brainresrev.2010.04.002. View

10.

Smith W, Margolis R, Li X, Troncoso J, Lee M, Dawson V . Alpha-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells. J Neurosci. 2005; 25(23):5544-52. PMC: 6724982. DOI: 10.1523/JNEUROSCI.0482-05.2005. View

11.

Sandal M, Valle F, Tessari I, Mammi S, Bergantino E, Musiani F . Conformational equilibria in monomeric alpha-synuclein at the single-molecule level. PLoS Biol. 2008; 6(1):e6. PMC: 2174973. DOI: 10.1371/journal.pbio.0060006. View

12.

Wilkinson K, Henley J . Mechanisms, regulation and consequences of protein SUMOylation. Biochem J. 2010; 428(2):133-45. PMC: 3310159. DOI: 10.1042/BJ20100158. View

13.

Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg M . alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002; 4(2):160-4. DOI: 10.1038/ncb748. View

14.

Junn E, Ronchetti R, Quezado M, Kim S, Mouradian M . Tissue transglutaminase-induced aggregation of alpha-synuclein: Implications for Lewy body formation in Parkinson's disease and dementia with Lewy bodies. Proc Natl Acad Sci U S A. 2003; 100(4):2047-52. PMC: 149956. DOI: 10.1073/pnas.0438021100. View

15.

Xu J, He Y, Qiang B, Yuan J, Peng X, Pan X . A novel method for high accuracy sumoylation site prediction from protein sequences. BMC Bioinformatics. 2008; 9:8. PMC: 2245905. DOI: 10.1186/1471-2105-9-8. View

16.

Tanaka M, Kim Y, Lee G, Junn E, Iwatsubo T, Mouradian M . Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective. J Biol Chem. 2003; 279(6):4625-31. DOI: 10.1074/jbc.M310994200. View

17.

Rodriguez M, Dargemont C, Hay R . SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting. J Biol Chem. 2001; 276(16):12654-9. DOI: 10.1074/jbc.M009476200. View

18.

Bennett M, Bishop J, Leng Y, Chock P, Chase T, Mouradian M . Degradation of alpha-synuclein by proteasome. J Biol Chem. 1999; 274(48):33855-8. DOI: 10.1074/jbc.274.48.33855. View

19.

Kahle P, Neumann M, Ozmen L, Muller V, Odoy S, Okamoto N . Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am J Pathol. 2001; 159(6):2215-25. PMC: 1850592. DOI: 10.1016/s0002-9440(10)63072-6. View

20.

Ryu J, Cho S, Park B, Lee D . Oxidative stress-enhanced SUMOylation and aggregation of ataxin-1: Implication of JNK pathway. Biochem Biophys Res Commun. 2010; 393(2):280-5. DOI: 10.1016/j.bbrc.2010.01.122. View