TMEM106B knockdown exhibits a neuroprotective effect in Parkinson's disease models via regulating autophagy-lysosome pathway.

Background: TMEM106B, a lysosomal transmembrane protein, has been reported to be associated with Parkinson's disease (PD). However, the precise physiopathologic mechanism of TMEM106B in PD remains unclear.

Objective: This study aimed to explore the influence of TMEM106B on the autophagy-lysosome pathway (ALP) in PD.

Methods: 55 patients with PD and 40 healthy controls were enrolled. RT-qPCR and ELISA were employed to assess the levels of TMEM106B. In vitro and in vivo models of PD, Lentivirus-shTMEM106B and AAV-shTMEM106B were used to knockdown the expression of TMEM106B. Behavioral experiments, western blot, immunofluorescence, and immunohistochemistry were used to detect the effect of TMEM106B on the ALP process.

Results: We found that the levels of TMEM106B were increased in the PD patients and PD models. TMEM106B knockdown markedly improved the motor deficits and tyrosine hydroxylase (TH) expression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice. TMEM106B knockdown promoted α-syn clearance by regulating the ALP process in MPP-induced SH-SY5Y cells and MPTP-treated mice. Further studies revealed that TMEM106B knockdown might activate ALP through activating AMPK-mTOR-TFEB axis. Furthermore, TMEM106B may play a vital role in the ALP by mediating the expression of TDP43.

Conclusions: Taken together, our study suggests that TMEM106B knockdown mediates the ALP pathway, leading to a decrease in α-syn, providing a new direction and perspective for the regulation of autophagy in PD.