Beyond the Basal Ganglia: Cerebellar Oligodendrocytic α-Synuclein Pathology and Dentate Nucleus Neuronal Hypertrophy in Parkinson's Disease

Abstract This study investigates cerebellar neuropathology in idiopathic Parkinson's disease (iPD), focusing on the dentate nucleus (DN) and its adjacent white matter (DN-WM). Historically, iPD research has centered on basal ganglia dysfunction and neuronal Lewy bodies. However, we present evidence of significant oligodendrocytic α-synuclein (α-syn) pathology and neuronal hypertrophy within the DN of iPD patients, expanding the traditional understanding of the disease beyond the nigrostriatal system. Using immunohistochemistry (IHC), we systematically assessed α-syn-positive inclusions in autopsy-confirmed iPD brains compared to controls. We identified prominent intracytoplasmic α-syn inclusions within oligodendrocytes in the peri-dental WM, distinct from classic neuronal Lewy bodies, which were largely absent in the dentate neurons. Stereology-based morphometric analyses revealed significant hypertrophy of DN neuronal soma, nuclei, and nucleoli in iPD subjects.These findings suggest that oligodendrocytic α-synucleinopathy and associated white matter dysfunction in the cerebellum may contribute to both motor and non-motor symptoms in iPD. This highlights a critical, often underappreciated, role for cerebellar oligodendrocytes in disease pathogenesis, opening new avenues for therapeutic strategies targeting glial cells and white matter integrity.