Multifaceted performances of α-synuclein in health and neurological diseases

The misfolding and accumulating α-synuclein (αSyn) is a central pathological hallmark of various neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Under physiological conditions, αSyn essential for normal synaptic functions primarily through its regulation of synaptic vesicle trafficking, clustering, and neurotransmitter release. However, in disease states, the accumulation of pathological αSyn disrupts intracellular proteostasis, by impairing the ubiquitin-proteasome system, autophagy-lysosomal degradation pathway and endo-lysosomal pathway. This disruption ultimately leads to synaptic dysfunction and neuronal death. Here, we summarize current insights into the physiological and pathological roles of αSyn, focusing on its post-translational modifications, dysregulation of protein quality control systems, prion-like cell-to-cell propagation, and liquid-liquid phase separation. We also discuss emerging therapeutic strategies that target abnormally aggregated αSyn. A comprehensive understanding of αSyn's multifaceted mechanisms is therefore critical for developing novel diagnostic biomarkers and effective therapeutics for α-synucleinopathies.