Postmortem analysis reveals alpha-synuclein inclusions in cerebellar oligodendrocytes, concurrent myelin rarefaction, and hypertrophy of dentate nucleus neurons in idiopathic Parkinson’s disease.

By implicating oligodendroglial alpha-synucleinopathy and impaired glial–neuronal metabolic coupling in cerebello–basal ganglia circuits, the study uncovers a novel, actionable mechanism with potential biomarker and therapeutic targets (oligodendrocytes/myelin and alpha-syn clearance) for PD.

Idiopathic Parkinson's disease (iPD) research has historically prioritized basal ganglia dysfunction and neuronal Lewy body pathology, often overlooking cerebellar and non-neuronal cells contributions. This study investigates cerebellar neuropathology in iPD, specifically focusing on neuronal and non-neuronal cells of the dentate nucleus (DN) and its adjacent white matter (DN-WM). We systematically assessed autopsy-confirmed iPD brains vs. age-matched controls using immunohistochemistry and stereology-based morphometry methods. The study evaluated α-synuclein pathology, other common age-related co-occurring pathologies (β-amyloid, Tau, neuroinflammation), myelin integrity (Luxol-Fast-Blue), and neuronal volumetric changes in the DN of the cerebellum. In iPD brains, we identified intracytoplasmic α-synuclein inclusions within oligodendrocytes across the peri-DN-WM. These inclusions were distinct from classic neuronal Lewy bodies (dense core with clearer halo), which were notably absent in the DN neurons. Concomitantly, we observed myelin rarefaction in the DN and the around WM area. Moreover, stereology-based morphometric analysis revealed a significant hypertrophy of DN neuronal soma (p < 0.05), nuclei (p < 0.0001), and nucleoli (p < 0.0001) in iPD vs. C subjects, suggesting a heightened metabolic state or compensatory stress response. These findings are novel and suggest that oligodendroglial α-synucleinopathy may be a contributing factor to cerebellar abnormalities and degeneration in iPD. Due to the recent identification of direct pathways between the DN and basal ganglia in primates and the DN primary dopaminergic modulatory function, these outcomes are of a special pathophysiological relevance. In fact, we hypothesize that this oligo-synucleinopathy WM deterioration compromises the glial-neuronal metabolic coupling and physiological transmission along the cerebello-basal ganglia-cortical loops. Moreover, these alterations could contribute to explain the broader spectrum motor and non-motor symptomatology observed in specific iPD subtypes.