Cerebellar α-synucleinopathy contributes to Parkinsonian gait and balance impairment in mouse models

Postural instability and gait difficulty (PIGD) represent a debilitating clinical subtype of Parkinson’s disease (PD) that is largely refractory to dopaminergic replacement therapy. While clinical imaging implies that the cerebellum is involved in these axial deficits, the specific contribution of cerebellar α-synuclein (α-syn) pathology to the onset and progression of PIGD remains unclear. To elucidate the pathological progression and functional consequences of cerebellar synucleinopathy, we employed both a global A53T α-syn transgenic mouse model and a viral-mediated, cerebellar nuclei (CN)-restricted A53T overexpression model. A53T transgenic mice developed progressive impairments in balance and gait coordination starting at 11 months, mirroring the clinical onset of axial symptoms. These deficits coincided with accumulation of phosphorylated α-syn (pSer129) in Purkinje cells, synapse-enriched regions of the granular layer, and CN neurons, accompanied by focal neurodegeneration and neuroinflammation. To determine whether focal cerebellar pathology is sufficient to drive these motor deficits, we selectively overexpressed A53T α-syn in CN neurons of adult wild-type mice. Our results showed that local pSer129-pathology in CN recapitulated key motor phenotypes of the transgenic model, including prolonged balance beam latency and significant gait abnormalities characterized by reduced stride length and walking speed. Furthermore, anterograde axonal transport of A53T α-syn to the substantia nigra pars compacta was detected; however, cell counting revealed no significant loss of dopaminergic neurons during the symptomatic phase. In conclusion, these findings provide causal evidence that cerebellar α-syn pathology emerges early, exhibits regional vulnerability, and independently drives PD-like gait and balance impairments. This study may provide insight into the pathological circuit mechanisms underlying the development of PIGD, and identifies cerebellar circuits as potential therapeutic targets for these refractory symptoms.