There is growing recognition in the field of neurodegenerative diseases that mixed proteinopathies are occurring at greater frequency than originally thought. This is particularly true for three amyloid proteins defining most of these neurological disorders, amyloid-beta (Aβ), tau, and alpha-synuclein (αSyn). The co-existence and often co-localization of aggregated forms of these proteins has led to the emergence of concepts positing molecular interactions and cross-seeding between Aβ, tau, and αSyn aggregates. Amongst this trio, αSyn has received particular attention in this context during recent years due to its ability to modulate Aβ and tau aggregation in vivo, to interact at a molecular level with Aβ and tau in vivo and to cross-seed tau in mice. Here we provide a comprehensive, critical, and accessible review about the expression, role and nature of endogenous soluble αSyn oligomers because of recent developments in the understanding of αSyn multimerization, misfolding, aggregation, cross-talk, spreading and cross-seeding in neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Alzheimer's disease, and Huntington's disease. We will also discuss our current understanding about the relative toxicity of endogenous αSyn oligomers in vivo and in vitro, and introduce potential opportunities to counter their deleterious effects.
Bibliographical noteFunding Information:
Aggregation of αSyn is a hallmark feature in synu-cleinopathies. Since the discovery of αSyn protein as the main component of the neuropathological lesions defining synucleinopathies, LB and LN, there has been a continuous effort to better understand the underlying mechanisms of these debilitating diseases. Despite significant advances made in recent years, the exact reasons behind the selective vulnerability of different neuronal and non-neuronal cell populations as well as brain regions to the aggregation of αSyn remain unknown. The implication of soluble αSyn oligomers in impairing multiple cellular processes has led to the consideration of such oligomeric assemblies as the main pathogenic entity in synucleinopathies. Hence, better understanding the molecular events leading to αSyn oligomer formation, seeding and propagation in vivo are of utmost This work was supported by grants from the National Institutes of Health (NIH) to SEL (RF1-AG044342, R21-AG065693, R01-NS092918, R01-AG062135 and R56-NS113549), to RK (R01-AG054025, R01-NS094557 and RF1-AG055771) and to UD (R01-NS099328). Additional support included start-up funds from the University of Minnesota Foundation and bridge funds from the Institute of Translational Neuroscience to SEL, grants from Gilson Longenbaugh Foundation and Mitchell Center for Neurodegenerative Diseases to RK. We thank the study participants and staff of the Rush Alzheimer’s Disease Center and its director Dr. David Bennett at Rush University.
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- neurodegenerative disease
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't
- Research Support, N.I.H., Extramural