Objective: To determine whether cerebellar α-synuclein (α-syn) pathology contributes to the onset and progression of postural instability and gait difficulty (PIGD)-like motor deficits in Parkinson’s disease (PD), and to clarify its pathological progression and functional consequences.

Background: PIGD is a disabling clinical subtype of PD that is often poorly responsive to dopaminergic replacement therapy. Although clinical imaging studies suggest cerebellar involvement in PIGD, the specific role of cerebellar α-syn pathology in the development of gait and balance impairment remains unclear.

Method: We employed both a global A53T α-syn transgenic mouse model and a viral-mediated, cerebellar nuclei (CN)-restricted A53T overexpression model.  Balance, gait, and pathological changes were assessed.

Results: A53T transgenic mice developed progressive impairments in balance and gait coordination beginning at 11 months of age, paralleling the emergence of axial motor symptoms. These behavioral deficits were accompanied by accumulation of pSer129 α-syn in Purkinje cells, synapse-rich regions of the granular layer, and CN neurons, together with focal neurodegeneration and neuroinflammation. To test whether focal cerebellar pathology is sufficient to induce these deficits, A53T α-syn was selectively overexpressed in CN neurons of adult wild-type mice. This manipulation reproduced key motor abnormalities observed in the transgenic model, including prolonged balance beam latency, reduced stride length, and decreased walking speed. Although anterograde axonal transport of A53T α-syn to the substantia nigra was detected, stereological analysis showed no significant loss of dopaminergic neurons.

Conclusion: These findings provide evidence that cerebellar α-syn pathology is sufficient to independently drive PD-like gait and balance impairments. The study highlights a potential pathological mechanism underlying PIGD and supports cerebellar circuits as promising therapeutic targets for these treatment-refractory axial symptoms.

References: 1. Li T, Le W, Jankovic J. Linking the cerebellum to Parkinson disease: an update. Nat Rev Neurol, 2023,19: 645-54.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cerebellar-%ce%b1-synucleinopathy-contributes-to-gait-and-balance-impairment-in-parkinsons-disease/