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Non-fibrillar Amyloidogenic Protein Assemblies - Common Cytotoxins Underlying Degenerative Diseases pp 189–216Cite as

Oligomers of α-Synuclein in the Pathogenesis of Parkinson’s Disease

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Abstract

Misfolding and subsequent self-assembly of proteins into various aggregates is a common molecular mechanism in a number of important human diseases. Understanding the peculiarities of the protein-misfolding processes is essential for the design of successful drugs that inhibit or reverse protein aggregation, leading to protein-misfolding pathologies. Protein aggregation is a complex process characterized by remarkable polymorphism, where soluble amyloid oligomers, amyloid fibrils, and amorphous aggregates are found as the final products. This polymorphism is associated with existence of multiple, independent, and competing assembly pathways leading to aggregation. Irrespectively of aggregation mechanisms, soluble oligomers inevitably form during the self-association processes. Some of these oligomers are now considered major initiators of the pathogenic neurodegenerative cascades in the corresponding diseases. However, not all oligomers are equally harmful, and several amyloidogenic proteins form non-toxic oligomers, some of which are efficient fibrillation inhibitors. Unfortunately, information on the structural properties of soluble oligomers and mechanisms of their formation, inter-conversion, and toxicity is sparse. This chapter provides an overview of some topics related to soluble oligomers and several illustrative examples of toxic, non-toxic, productive, and off-pathway amyloid oligomers. The peculiarities of soluble oligomers of α-synuclein and its relation to the pathogenesis of Parkinson’s disease are also discussed.

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Abbreviations

AD:

Alzheimer disease

ADDL:

Aβ-derived diffusible ligand

AFM:

Atomic-force microscopy

AL amyloidosis:

Light-chain-associated amyloidosis

ANS:

8-anilinonaphthalenesulfonic acid

APP:

β-amyloid precursor protein

CD:

Circular dichroism

CJD:

Creutzfeldt–Jakob disease

DLB:

Dementia with Lewy bodies

DLBD:

Diffuse Lewy-body disease

EM:

Electron microscopy

FFI:

Fatal familial insomnia

FTIR:

Fourier-transform infrared spectroscopy

GSS:

Gerstmann–Sträussler–Scheinker syndrome

HD:

Huntington disease

LCDD:

Light-chain-deposition disease

LBVAD:

Lewy-body variant of Alzheimer’s disease

LTP:

Long-term potentiation

MSA:

Multiple-system atrophy

MW:

Molecular weight

NFT:

Neurofibrillary tangle

NIID:

Neuronal intranuclear inclusion disease

PD:

Parkinson’s disease

PHF:

Paired helical filaments

PrPC :

Cellular form of the prion protein

PrPSc :

Scrapie form of the prion protein

SBMA:

Spinal and bulbar muscular atrophy

SCA:

Spinocerebellar ataxia

ThT:

Thioflavin T

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Acknowledgements

This work was supported in part by the Program of the Russian Academy of Sciences for the “Molecular and cellular biology” (V.N.U.), by grants R01 LM007688-01A1 (V.N.U.) and GM071714-01A2 (V.N.U.) from the National Institutes of Health and the grant EF 0849803 (V.N.U.) from the National Science Foundation. We gratefully acknowledge support of the IUPUI Signature Centers Initiative.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, 95064, USA

    Dong-Pyo Hong & Wenbo Zhou

  2. Research Center for Protein Chemistry, Brown Foundation Institute of Molecular Medicine and the Department of Biochemistry and Molecular Biology, The University of Texas, Houston, TX, 77030, USA

    Dong-Pyo Hong

  3. Molecular Kinetics, Inc., 6201 La Pas Trail, Suite 160, Indianapolis, IN, 46268, USA

    Aaron Santner

  4. Department of Molecular Medicine, University of South Florida, Tampa, FL, 33612, USA

    Vladimir N. Uversky

  5. Institute for Intrinsically Disordered Protein Research, Center for Computational Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 410 W. 10th Street, HS 5009, Indianapolis, IN, 46202, USA

    Vladimir N. Uversky

  6. Institute for Biological Instrumentation, Russian Academy of Sciences, 142290, Pushchino, Moscow Region, Russia

    Vladimir N. Uversky

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  1. Dong-Pyo Hong
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  2. Wenbo Zhou
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  3. Aaron Santner
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  4. Vladimir N. Uversky
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Correspondence to Vladimir N. Uversky .

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  1. , Research School of Biology, Australian National University, Linnaeus Way, Canberra, 0200, Aust Capital Terr, Australia

    Farid Rahimi

  2. , Neurology, University of California at Los Angeles, Charles E. Young Drive South 635, Los Angeles, 90095-7334, California, USA

    Gal Bitan

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Hong, DP., Zhou, W., Santner, A., Uversky, V.N. (2012). Oligomers of α-Synuclein in the Pathogenesis of Parkinson’s Disease. In: Rahimi, F., Bitan, G. (eds) Non-fibrillar Amyloidogenic Protein Assemblies - Common Cytotoxins Underlying Degenerative Diseases. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2774-8_6

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