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

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2024-10-28 DOI:10.1016/j.bbadis.2024.167553

Yumei Liu, Kunpeng Qin, Kaixin Dou, Jiwen Ren, Binghui Hou, Anmu Xie

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引用次数: 0

Abstract

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.

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通过调节自噬-溶酶体通路，敲除 TMEM106B 可在帕金森病模型中发挥神经保护作用

背景据报道，溶酶体跨膜蛋白TMEM106B与帕金森病（PD）有关。本研究旨在探讨 TMEM106B 对帕金森病自噬-溶酶体途径（ALP）的影响。采用 RT-qPCR 和 ELISA 方法评估 TMEM106B 的水平。在体外和体内PD模型中，使用慢病毒-shTMEM106B和AAV-shTMEM106B敲除TMEM106B的表达。结果我们发现，TMEM106B在PD患者和PD模型中的水平均升高。TMEM106B的敲除明显改善了1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）缺失小鼠的运动障碍和酪氨酸羟化酶（TH）的表达。在MPP+诱导的SH-SY5Y细胞和MPTP处理的小鼠中，TMEM106B敲除可通过调节ALP过程促进α-syn的清除。进一步研究发现，TMEM106B敲除可能通过激活AMPK-mTOR-TFEB轴来激活ALP。此外，TMEM106B 可能通过介导 TDP43 的表达在 ALP 中发挥重要作用。结论综上所述，我们的研究表明，TMEM106B敲除可介导ALP通路，导致α-syn的减少，这为自噬在帕金森病中的调控提供了一个新的方向和视角。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.