TFE3-mediated neuroprotection: Clearance of aggregated α-synuclein and accumulated mitochondria in the AAV-α-synuclein model of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions containing aggregated α-synuclein (α-Syn). While the pathology of PD is multifaceted, the aggregation of α-Syn and mitochondrial dysfunction are well-established hallmarks in its pathogenesis. Recently, TFE3, a transcription factor, has emerged as a regulator of autophagy and metabolic processes. However, it remains unclear whether TFE3 can facilitate the degradation of α-Syn and regulate mitochondrial metabolism specifically in dopaminergic neurons. In this study, we demonstrate that TFE3 overexpression significantly mitigates the loss of dopaminergic neurons and reduces the decline in tyrosine hydroxylase-positive fiber density, thereby restoring motor function in an α-Syn overexpression model of PD. Mechanistically, TFE3 overexpression reversed α-Syn-mediated impairment of autophagy, leading to enhanced α-Syn degradation and reduced aggregation. Additionally, TFE3 overexpression inhibited α-Syn propagation. TFE3 overexpression also reversed the down-regulation of Parkin, promoting the clearance of accumulated mitochondria, and restored the expression of PGC1-α and TFAM, thereby enhancing mitochondrial biogenesis in the adeno-associated virus-α-Syn model. These findings further underscore the neuroprotective role of TFE3 in PD and provide insights into its underlying mechanisms, suggesting TFE3 as a potential therapeutic target for PD.