Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder, is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta, leading to various motor and non-motor disabilities. Its high prevalence and significant impact on quality of life underscore the urgent need for innovative treatments.

This study investigated the post-developmental role of Nato3, a crucial transcription factor for midbrain DA neurogenesis, using a mouse model with conditional Nato3 ablation (Nato3 cKO) in differentiated DA neurons. Employing immunohistochemistry, electron microscopy, RNA-sequencing, and behavioral assays, we found that Nato3 cKO mice recapitulate PD-like symptoms, including progressive locomotor decline, loss of mitochondrial integrity, and autophagy defects.

Furthermore, human NATO3 overexpression ameliorated cellular phenotypes associated with PD pathology, suggesting NATO3's involvement in autophagy-lysosomal system dynamics and mitochondrial health. These findings provide insights into NATO3's role in PD pathology and potential therapeutic targets.