Neuroprotection Across Cerebellar and Nigrostriatal Degeneration: Translational Insights from Parkinson's Disease to Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) and Parkinson's disease (PD) have traditionally been conceptualized as distinct neurodegenerative movement disorders involving cerebellar and nigrostriatal circuits, respectively. However, increasing clinical, neuroimaging, and neuropathological evidence supports some commonneurodegenerative mechanisms. In PD, beyond dopaminergic degeneration, alterations in cerebellar structure and function contribute to both motor and non-motor manifestations, highlighting the functional integration between basal ganglia and cerebellar networks. At the molecular level, both disorders converge on common pathogenic mechanisms, including mitochondrial dysfunction, oxidative stress, impaired proteostasis, calcium dysregulation, and neuroinflammation. These shared pathways provide a strong rationale for developing neuroprotective strategies that extend beyond disease-specific targets. Nevertheless, despite extensive research, disease-modifying therapies remain elusive, particularly due to the complexity of neurodegenerative processes, clinical heterogeneity, and the lack of sensitive biomarkers for early disease stages. Insights derived from PD research indicate that single-target approaches are insufficient to halt disease progression, supporting the emergence of multi-target and systems-based therapeutic strategies. Within this framework, spinocerebellar ataxias, mainly SCA2 should be reconsidered as part of a broader spectrum of network neurodegeneration, in which cerebellar and extrapyramidal systems are dynamically interconnected. Overall, this integrative perspective highlights the importance of early intervention, biomarker-driven clinical trial design, and the development of therapies targeting convergent pathogenic mechanisms. Such an approach may ultimately enable the identification of effective disease-modifying strategies for SCA2 and related neurodegenerative disorders.