α-Synuclein oligomers and clinical implications for Parkinson disease

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.

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).