TFE3 Regulates Microglial Phagocytosis and Inflammation in MPTP-induced Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disease. Our previous single-cell sequencing results suggested that Transcription Factor E3 (TFE3) was only differentially expressed in microglia in the MPTP mouse model. However, the functional role of microglial TFE3 in PD pathogenesis remains unclear. First, motor function was assessed in MPTP mice following TFE3 overexpression in substantia nigra microglia. Second, RNA-seq was used to identify the function of TFE3 in microglia, and the molecular mechanism was verified both in vivo and in vitro. Finally, we investigated whether TFE3 nuclear translocation affects its transcriptional activity and subsequently influences microglia in vitro. Overexpression of TFE3 in substantia nigra microglia could alleviate PD-related phenotypes. RNA-seq revealed that TFE3 regulates microglial phagocytosis and inflammation. Mechanistically, TFE3 affects these functions by regulating the expression of Mer receptor tyrosine kinase (Mertk) and lysosomal-associated membrane protein 1 (Lamp1). Finally, Rapamycin could activate the nuclear translocation of TFE3 and enhance phagocytosis and alleviate inflammation of microglia. Our findings demonstrate that Rapamycin activates TFE3, which in turn upregulates the expression of Mertk and Lamp1 in the substantia nigra. This TFE3-mediated pathway plays a critical role in regulating microglial phagocytosis and inflammation in the PD model.