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

## TL;DR

This review explores how alpha-synuclein contributes to various neurodegenerative diseases through complex interactions in different brain cells and environments.

## Contribution

The paper introduces a multidimensional framework linking alpha-synuclein biology to disease-specific outcomes in synucleinopathies.

## Key findings

- Alpha-synuclein pathology varies based on cell type, subcellular location, and post-translational modifications.
- Disease-specific manifestations arise from interactions between alpha-synuclein and co-pathologies in neural circuits.
- Understanding these interactions can guide the development of precision therapies and biomarkers for synucleinopathies.

## Abstract

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 suggest that αSyn-driven disease emerges within specific neural circuits through the combined effects of cell-type-specific roles, subcellular environments, post-translational modifications (PTMs), and co-pathology. These interacting and additive dimensions, rather than αSyn alone, generate the pathological diversity, shaping 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 (astrocytes, oligodendrocytes, and microglia), its compartment-dependent (e.g., synaptic and nuclear) functions, and the molecular transitions (e.g., mediated by pS129) 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 on αSyn biology can inform the development of next-generation biomarkers that support precision therapies across distinct disorders.