Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China.
Biochim Biophys Acta Mol Basis Dis. 2025 Jan;1871(1):167553. doi: 10.1016/j.bbadis.2024.167553. Epub 2024 Oct 28.
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.
This study aimed to explore the influence of TMEM106B on the autophagy-lysosome pathway (ALP) in PD.
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.
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.
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.
TMEM106B 是一种溶酶体跨膜蛋白，已被报道与帕金森病（PD）有关。然而，TMEM106B 在 PD 中的精确病理生理机制仍不清楚。
本研究旨在探讨 TMEM106B 对 PD 中自噬溶酶体途径（ALP）的影响。
纳入 55 例 PD 患者和 40 例健康对照者。采用 RT-qPCR 和 ELISA 检测 TMEM106B 水平。利用 PD 的体外和体内模型，采用慢病毒-shTMEM106B 和 AAV-shTMEM106B 敲低 TMEM106B 的表达。行为实验、western blot、免疫荧光和免疫组化用于检测 TMEM106B 对 ALP 过程的影响。
我们发现 PD 患者和 PD 模型中 TMEM106B 的水平升高。TMEM106B 敲低显著改善了 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）损伤小鼠的运动缺陷和酪氨酸羟化酶（TH）表达。TMEM106B 敲低通过调节 MPP 诱导的 SH-SY5Y 细胞和 MPTP 处理的小鼠中的 ALP 过程促进 α-syn 的清除。进一步的研究表明，TMEM106B 敲低可能通过激活 AMPK-mTOR-TFEB 轴来激活 ALP。此外，TMEM106B 可能通过调节 TDP43 的表达在 ALP 中发挥重要作用。
综上所述，我们的研究表明，TMEM106B 敲低介导了 ALP 途径，导致 α-syn 的减少，为 PD 中自噬的调节提供了新的方向和视角。
