Frontotemporal dementia causative CHMP2B impairs neuronal endolysosomal traffic-rescue by TMEM106B knockdown.
Frontotemporal dementia causative CHMP2B impairs neuronal endolysosomal traffic-rescue by TMEM106B knockdown.
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DOI：
10.1093/brain/awy284
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发表时间：
2018-12-01
期刊：
影响因子：
--
通讯作者：
Isaacs AM
中科院分区：
文献类型：
--
作者：
Clayton EL;Milioto C;Muralidharan B;Norona FE;Edgar JR;Soriano A;Jafar-Nejad P;Rigo F;Collinge J;Isaacs AM
有关本文的科学评论，请参阅 Bechek 和 Gitler (doi:)。内体相关蛋白 CHMP2B 的突变会导致额颞叶痴呆 (FTD)。克莱顿等人。报告了 CHMP2B 介导的神经元功能障碍的机制以及针对 TMEM106B 基因（FTD 的主要危险因素）的潜在治疗策略。靶向 TMEM106B 可能与广泛的 FTD 相关。内体相关蛋白 CHMP2B 的突变会导致额颞叶痴呆，并导致神经元中的溶酶体储存病理学。我们在此报告，突变体 CHMP2B 的生理水平会导致神经元树突内内溶酶体的数量减少并显着受损，并伴有树突分支增加。从机制上讲，这是由于突变体 CHMP2B 稳定掺入神经元内溶酶体，我们表明这使得它们无法在树突内运输。该缺陷是由于突变体 CHMP2B 无法募集 ATP 酶 VPS4，而该酶是从内体膜释放 CHMP2B 所必需的。引人注目的是，通过针对经过充分验证的额颞叶痴呆风险因子 TMEM106B（编码内溶酶体蛋白）的反义寡核苷酸治疗，受损的运输和增加的树突分支都得到了挽救。这表明降低 TMEM106B 水平可以恢复额颞叶痴呆的内体健康。由于 TMEM106B 是由 C9orf72 和颗粒体蛋白前体突变引起的额颞叶痴呆的危险因素，并且反义寡核苷酸显示出作为神经退行性疾病治疗药物的前景，因此我们的数据表明了一种潜在的新策略，用于治疗与内溶酶体功能障碍相关的各种额颞叶痴呆。
See Bechek and Gitler (doi:) for a scientific commentary on this article. Mutations in the endosome-associated protein CHMP2B cause frontotemporal dementia (FTD). Clayton et al. report a mechanism for CHMP2B-mediated neuronal dysfunction and a potential therapeutic strategy targeting the TMEM106B gene, a major risk factor for FTD. Targeting TMEM106B may be relevant to a broad range of FTDs. Mutations in the endosome-associated protein CHMP2B cause frontotemporal dementia and lead to lysosomal storage pathology in neurons. We here report that physiological levels of mutant CHMP2B causes reduced numbers and significantly impaired trafficking of endolysosomes within neuronal dendrites, accompanied by increased dendritic branching. Mechanistically, this is due to the stable incorporation of mutant CHMP2B onto neuronal endolysosomes, which we show renders them unable to traffic within dendrites. This defect is due to the inability of mutant CHMP2B to recruit the ATPase VPS4, which is required for release of CHMP2B from endosomal membranes. Strikingly, both impaired trafficking and the increased dendritic branching were rescued by treatment with antisense oligonucleotides targeting the well validated frontotemporal dementia risk factor TMEM106B, which encodes an endolysosomal protein. This indicates that reducing TMEM106B levels can restore endosomal health in frontotemporal dementia. As TMEM106B is a risk factor for frontotemporal dementia caused by both C9orf72 and progranulin mutations, and antisense oligonucleotides are showing promise as therapeutics for neurodegenerative diseases, our data suggests a potential new strategy for treating the wide range of frontotemporal dementias associated with endolysosomal dysfunction.
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