Alpha-Synuclein in Neurodegeneration: From Shared Biology to Disease-Specific Phenotypes

Alpha-synuclein (αSyn) is one of the most abundant proteins in the nervous system and is currently associated with devastating synucleinopathies, yet its biology extends far beyond this. In this review, we outline a unified model suggesting that αSyn‑driven disease emerges within specific neural circuits through the combined effects of cell‑type‑specific roles, subcellular environments, and post‑translational modifications. These interacting and additive dimensions generate strain diversity within regions of co-pathology and, collectively, rather than αSyn alone, shape whether pathology manifests as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), or mixed dementia phenotypes. We integrate recent advances on the physiological roles of αSyn in neurons and glia, its compartment-dependent functions, and the molecular transitions that convert functional assemblies into pathogenic conformers. Building on this foundation, we outline mechanisms through which these factors contribute to disease-specific vulnerability, progression, and clinical heterogeneity. Finally, we highlight how this multidimensional perspective can inform the development of next-generation biomarkers and precision therapies tailored to αSyn biology across distinct disorders.