Neuronal vulnerability in Parkinson's disease: insights from murine α-synuclein pathology models

Parkinson's disease (PD) is characterised by the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Lewy bodies- the defining neuropathological hallmark of PD-are chiefly composed of aggregated forms of α-synuclein (α-syn). Despite the widespread presence of α-syn pathology, neurodegeneration is often selective, and the mechanisms underlying the vulnerability of specific neuronal populations in PD remain poorly understood. This review critically evaluates α-syn-based models of PD, with a focus on murine systems, to determine how they have illuminated the cellular and molecular determinants of neuronal susceptibility. Across murine α-syn pathology models, degeneration reliably affects dopaminergic neurons (TH⁺) in SNpc, with preferential vulnerability of aldehyde dehydrogenase 1 family member A1^- (ALDH1A1^-) neurons in the dorsal SNpc, as well as noradrenergic and cholinergic (ChAT⁺) neurons, and parvalbuminergic interneurons, depending on the experimental context. In these models, degeneration is accompanied by mitochondrial and lysosomal dysfunction, calcium dysregulation, presynaptic failure, and neuroinflammatory activation. This review integrates transcriptomic and proteomic data across murine α-synuclein models, revealing differences in selective neuronal vulnerability across models depending on spatiotemporal context and interplay between intrinsic neuronal properties and extrinsic factors. This review paper underscores the need for stage-resolved mapping of vulnerable neuronal and non-neuronal populations in PD and, as well as careful alignment of model selection with the specific mechanistic questions under investigation. It also highlights the need for further single cell and spatiotemporally resolved in vivo studies using reliable molecular markers.