The Many Faces of Parkinsonism: Dissecting Clinical and Molecular Overlap in Multiple System Atrophy and Parkinson's Disease

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder with heterogeneous clinical manifestations, most commonly parkinsonism (MSA-P) or cerebellar ataxia (MSA-C). MSA-P shares many motor features with Parkinson’s disease (PD), including bradykinesia and rigidity, which often leads to misdiagnosis in early stages. However, disease trajectory, therapeutic responsiveness, and underlying pathology diverge substantially between MSA and PD. In this perspective, we examine the clinical and molecular boundaries between these disorders, with an emphasis on motor phenotypes, diagnostic pitfalls, and emerging translational approaches. We review the limited dopaminergic responsiveness in MSA compared to PD, highlight the geographical variability in MSA phenotypes, and discuss how autonomic dysfunction and cerebellar features contribute to early diagnostic clues. Advances in neuroimaging and fluid biomarkers, such as neurofilament light chain and α-synuclein seeding assays, are beginning to refine differential diagnosis, though clinical utility remains limited in prodromal stages. On a molecular level, PD is increasingly defined by synaptic and extracellular matrix dysfunction in dopaminergic neurons, while MSA pathogenesis is driven by α-synuclein aggregation within oligodendrocytes and lipid metabolic disturbances. Patient-derived induced pluripotent stem cell (iPSC) models have been instrumental in capturing these divergent mechanisms, underscoring the necessity for tailored therapeutic strategies.