Loss of TMEM106B exacerbates C9ALS/FTD DPR pathology by disrupting autophagosome maturation.
Loss of TMEM106B exacerbates C9ALS/FTD DPR pathology by disrupting autophagosome maturation.
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DOI：
10.3389/fncel.2022.1061559
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发表时间：
2022
影响因子：
5.3
通讯作者：
De Vos, Kurt J.
中科院分区：
文献类型：
--
作者：
Bauer, Claudia S.;Webster, Christopher P.;Shaw, Allan C.;Kok, Jannigje R.;Castelli, Lydia M.;Lin, Ya-Hui;Smith, Emma F.;Illanes-Alvarez, Francisco;Higginbottom, Adrian;Shaw, Pamela J.;Azzouz, Mimoun;Ferraiuolo, Laura;Hautbergue, Guillaume M.;Grierson, Andrew J.;De Vos, Kurt J.
由溶酶体功能障碍和相关的自噬损伤引起的蛋白质稳态破坏是肌萎缩侧索硬化症和额颞叶痴呆（ALS/FTD）的主要病理学。ALS/FTD最常见的遗传原因是C9 orf 72中的G4 C2六核苷酸重复扩增（C9 ALS/FTD）。G4 C2重复转录物的重复相关非AUG（RAN）翻译产生二肽重复（DPR）蛋白，其已被证明是有毒的，并可能导致疾病病因。TMEM 106 B中的遗传变异与C9 ALS/FTD中的额颞叶变性伴TDP-43病理和疾病进展相关。TMEM 106 B编码一种功能未知的溶酶体跨膜蛋白，其参与溶酶体生物学的各个方面。TMEM 106 B变体如何影响C9 ALS/FTD尚不清楚，但已与TMEM 106 B蛋白水平的变化相关。在此，我们研究了TMEM 106 B在C9 ALS/FTD DPR病理学背景下的功能。我们报告，TMEM 106 B表达的敲低通过损害自噬加剧了C9 ALS/FTD相关细胞毒性DPR蛋白在表达RAN翻译或AUC驱动的DPR的细胞模型中以及在C9 ALS/FTD衍生的具有内源性G4 C2扩增的iAstrocytes中的积累。TMEM 106 B的缺失通过破坏自噬体至自溶酶体成熟而导致自噬晚期的阻断，这与受损的溶酶体酸化、降低的组织蛋白酶活性和溶酶体的核外聚集一致。溶酶体聚集需要Rab 7A，并且与减少Arl 8b介导的溶酶体向细胞外周的顺行运输相一致。在TMEM 106 B缺陷细胞中增加Arl 8b活性不仅恢复了溶酶体的分布，而且完全挽救了自噬和DPR蛋白积累。因此，我们鉴定了TMEM 106 B通过Ar 18 b在自噬体成熟中的新功能。我们的研究结果表明，TMEM 106 B变体可能通过调节DPR蛋白的自噬清除来修饰C9 ALS/FTD。因此，当考虑将改变TMEM 106 B表达水平作为ALS/FTD的治疗方法时，应谨慎。
Disruption to protein homeostasis caused by lysosomal dysfunction and associated impairment of autophagy is a prominent pathology in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). The most common genetic cause of ALS/FTD is a G4C2 hexanucleotide repeat expansion in C9orf72 (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of G4C2 repeat transcripts gives rise to dipeptide repeat (DPR) proteins that have been shown to be toxic and may contribute to disease etiology. Genetic variants in TMEM106B have been associated with frontotemporal lobar degeneration with TDP-43 pathology and disease progression in C9ALS/FTD. TMEM106B encodes a lysosomal transmembrane protein of unknown function that is involved in various aspects of lysosomal biology. How TMEM106B variants affect C9ALS/FTD is not well understood but has been linked to changes in TMEM106B protein levels. Here, we investigated TMEM106B function in the context of C9ALS/FTD DPR pathology. We report that knockdown of TMEM106B expression exacerbates the accumulation of C9ALS/FTD-associated cytotoxic DPR proteins in cell models expressing RAN-translated or AUG-driven DPRs as well as in C9ALS/FTD-derived iAstrocytes with an endogenous G4C2 expansion by impairing autophagy. Loss of TMEM106B caused a block late in autophagy by disrupting autophagosome to autolysosome maturation which coincided with impaired lysosomal acidification, reduced cathepsin activity, and juxtanuclear clustering of lysosomes. Lysosomal clustering required Rab7A and coincided with reduced Arl8b-mediated anterograde transport of lysosomes to the cell periphery. Increasing Arl8b activity in TMEM106B-deficient cells not only restored the distribution of lysosomes, but also fully rescued autophagy and DPR protein accumulation. Thus, we identified a novel function of TMEM106B in autophagosome maturation via Arl8b. Our findings indicate that TMEM106B variants may modify C9ALS/FTD by regulating autophagic clearance of DPR proteins. Caution should therefore be taken when considering modifying TMEM106B expression levels as a therapeutic approach in ALS/FTD.
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影响因子：
9.2
作者：
Bright, Nicholas A.;Davis, Luther J.;Luzio, J. Paul
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