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α-Synuclein misfolding and aggregation: Implications in Parkinson's disease pathogenesis
Surabhi Mehra1, Shruti Sahay1, Samir K Maji1
1Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai 400076, India.
Biochimica Et Biophysica Acta. Proteins and Proteomics
|March 12, 2019
Summary
Alpha-synuclein (α-Syn) aggregation is central to Parkinson's disease (PD) pathogenesis. This review explores α-Syn structure, function, and factors influencing aggregation, aiming to identify therapeutic targets for synucleinopathies.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Alpha-synuclein (α-Syn) aggregation into Lewy bodies is a hallmark of Parkinson's disease (PD).
- Mutations in α-Syn are linked to familial PD, suggesting its critical role in pathogenesis.
- Oligomeric α-Syn species are implicated as potent neurotoxic agents in PD, though difficult to characterize.
Purpose of the Study:
- To review the structural and functional aspects of α-Syn.
- To explore factors contributing to synucleinopathies.
- To identify novel therapeutic targets for PD and related protein aggregation disorders.
Main Methods:
- Literature review focusing on structural and biophysical properties of α-Syn.
- Analysis of existing evidence on α-Syn aggregation mechanisms and neurotoxicity.
- Synthesis of information on conformational plasticity and environmental influences on α-Syn.
Main Results:
- α-Syn aggregation is strongly associated with PD pathogenesis.
- Oligomers represent early, toxic species, while fibrils act as infectious agents.
- α-Syn exhibits significant conformational plasticity, influenced by environmental factors.
Conclusions:
- Understanding α-Syn's structural dynamics and aggregation factors is crucial for developing effective therapies.
- Targeting α-Syn aggregation pathways offers potential for treating Parkinson's disease and other synucleinopathies.
- Further research into α-Syn's heterogeneous forms may reveal specific therapeutic strategies.