α-Synuclein oligomers and clinical implications for Parkinson disease - PubMed (original) (raw)
Review
α-Synuclein oligomers and clinical implications for Parkinson disease
Lorraine V Kalia et al. Ann Neurol. 2013 Feb.
Abstract
Protein aggregation within the central nervous system has been recognized as a defining feature of neurodegenerative diseases since the early 20th century. Since that time, there has been a growing list of neurodegenerative disorders, including Parkinson disease, which are characterized by inclusions of specific pathogenic proteins. This has led to the long-held dogma that these characteristic protein inclusions, which are composed of large insoluble fibrillar protein aggregates and visible by light microscopy, are responsible for cell death in these diseases. However, the correlation between protein inclusion formation and cytotoxicity is inconsistent, suggesting that another form of the pathogenic proteins may be contributing to neurodegeneration. There is emerging evidence implicating soluble oligomers, smaller protein aggregates not detectable by conventional microscopy, as potential culprits in the pathogenesis of neurodegenerative diseases. The protein α-synuclein is well recognized to contribute to the pathogenesis of Parkinson disease and is the major component of Lewy bodies and Lewy neurites. However, α-synuclein also forms oligomeric species, with certain conformations being toxic to cells. The mechanisms by which these α-synuclein oligomers cause cell death are being actively investigated, as they may provide new strategies for diagnosis and treatment of Parkinson disease and related disorders. Here we review the possible role of α-synuclein oligomers in cell death in Parkinson disease and discuss the potential clinical implications.
Copyright © 2012 American Neurological Association.
Figures
Figure 1. α-Syn oligomers and Parkinson disease
(A) Formation and toxicity of α-syn oligomers. Protein aggregation in neurodegenerative diseases is initiated by aberrant protein folding which leads to the formation of oligomers and eventually amyloid fibrils and inclusions bodies (blue arrows). Certain oligomeric species are toxic to cells by mechanisms that include (1) impairment of proteostasis, (2) chronic endoplasmic reticulum (ER) stress, (3) pore formation, (4) glutamate receptor dysfunction, (5) seeding with (6) prion-like transmission (red arrows), all of which may combine in the pathogenic process of cell death and transmission. Endogenous cellular systems which can reduce oligomer levels are the chaperone network, the ubiquitin-proteasomal system (UPS), and the autophagy-lysosomal pathway (ALP) (green arrows). (B) Potential treatment strategies which reduce toxic α-syn oligomers to slow or prevent neurodegeneration. These strategies target different steps along the protein aggregation pathway, as well as intracellular and/or extracellular pools of α-syn oligomers. The primary goal of treatment is to reduce toxic oligomer levels directly or indirectly by preventing oligomer formation, disrupting already formed oligomers, promoting degradation of toxic oligomers or conversion of toxic oligomers to non-toxic oligomers, and sequestering or clearing oligomers by antibody or cell-based mechanisms to prevent cell-to-cell transmission (black dotted lines).
Similar articles
- Proteasome inhibition induces α-synuclein SUMOylation and aggregate formation.
Kim YM, Jang WH, Quezado MM, Oh Y, Chung KC, Junn E, Mouradian MM. Kim YM, et al. J Neurol Sci. 2011 Aug 15;307(1-2):157-61. doi: 10.1016/j.jns.2011.04.015. Epub 2011 Jun 8. J Neurol Sci. 2011. PMID: 21641618 Free PMC article. - Pathological interface between oligomeric alpha-synuclein and tau in synucleinopathies.
Sengupta U, Guerrero-Muñoz MJ, Castillo-Carranza DL, Lasagna-Reeves CA, Gerson JE, Paulucci-Holthauzen AA, Krishnamurthy S, Farhed M, Jackson GR, Kayed R. Sengupta U, et al. Biol Psychiatry. 2015 Nov 15;78(10):672-83. doi: 10.1016/j.biopsych.2014.12.019. Epub 2015 Jan 9. Biol Psychiatry. 2015. PMID: 25676491 - [The role of alpha-synuclein in Parkinson's disease].
Miklya I, Pencz N, Hafenscher F, Göltl P. Miklya I, et al. Neuropsychopharmacol Hung. 2014 Jun;16(2):77-84. Neuropsychopharmacol Hung. 2014. PMID: 24978050 Review. Hungarian. - Defining α-synuclein species responsible for Parkinson's disease phenotypes in mice.
Froula JM, Castellana-Cruz M, Anabtawi NM, Camino JD, Chen SW, Thrasher DR, Freire J, Yazdi AA, Fleming S, Dobson CM, Kumita JR, Cremades N, Volpicelli-Daley LA. Froula JM, et al. J Biol Chem. 2019 Jul 5;294(27):10392-10406. doi: 10.1074/jbc.RA119.007743. Epub 2019 May 29. J Biol Chem. 2019. PMID: 31142553 Free PMC article. - α-Synuclein in Extracellular Vesicles: Functional Implications and Diagnostic Opportunities.
Lööv C, Scherzer CR, Hyman BT, Breakefield XO, Ingelsson M. Lööv C, et al. Cell Mol Neurobiol. 2016 Apr;36(3):437-48. doi: 10.1007/s10571-015-0317-0. Epub 2016 Mar 18. Cell Mol Neurobiol. 2016. PMID: 26993503 Review.
Cited by
- ProSol-multi: Protein solubility prediction via amino acids multi-level correlation and discriminative distribution.
Ghafoor H, Asim MN, Ibrahim MA, Dengel A. Ghafoor H, et al. Heliyon. 2024 Aug 22;10(17):e36041. doi: 10.1016/j.heliyon.2024.e36041. eCollection 2024 Sep 15. Heliyon. 2024. PMID: 39281576 Free PMC article. - High frequency electrical stimulation reduces α-synuclein levels and α-synuclein-mediated autophagy dysfunction.
George J, Shafiq K, Kapadia M, Kalia LV, Kalia SK. George J, et al. Sci Rep. 2024 Jul 12;14(1):16091. doi: 10.1038/s41598-024-64131-3. Sci Rep. 2024. PMID: 38997273 Free PMC article. - 4-Oxo-2-Nonenal- and Agitation-Induced Aggregates of α-Synuclein and Phosphorylated α-Synuclein with Distinct Biophysical Properties and Biomedical Applications.
Wang T, Liu W, Zhang Q, Jiao J, Wang Z, Gao G, Yang H. Wang T, et al. Cells. 2024 Apr 24;13(9):739. doi: 10.3390/cells13090739. Cells. 2024. PMID: 38727274 Free PMC article. - Mitophagy Upregulation Occurs Early in the Neurodegenerative Process Mediated by α-Synuclein.
Hui S, George J, Kapadia M, Chau H, Bariring Z, Earnshaw R, Shafiq K, Kalia LV, Kalia SK. Hui S, et al. Mol Neurobiol. 2024 Apr 6. doi: 10.1007/s12035-024-04131-6. Online ahead of print. Mol Neurobiol. 2024. PMID: 38581539 - Effects of latroeggtoxin-VI on dopamine and α-synuclein in PC12 cells and the implications for Parkinson's disease.
Yu D, Wang H, Zhai Y, Lei Z, Sun M, Chen S, Yin P, Wang X. Yu D, et al. Biol Res. 2024 Mar 16;57(1):9. doi: 10.1186/s40659-024-00489-y. Biol Res. 2024. PMID: 38491377 Free PMC article.
References
- Lewy F. Paralysis agitans. In: Lewandowski M, editor. Handbuch der Neurologie. Berlin: Springer; 1912. pp. 920–933.
- Jakes R, Spillantini MG, Goedert M. Identification of two distinct synucleins from human brain. FEBS Lett. 1994;345:27–32. - PubMed
- Chandra S, Gallardo G, Fernandez-Chacon R, et al. Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell. 2005;123:383–396. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous