Department of Pharmacology, UCL School of Pharmacy, London, UK.
Currently at UK Dementia Research Institute at King's College London, London, UK.
J Neurochem. 2022 Feb;160(3):412-425. doi: 10.1111/jnc.15551. Epub 2021 Dec 11.
Mutations in the ESCRT-III subunit CHMP2B cause frontotemporal dementia (FTD) and lead to impaired endolysosomal trafficking and lysosomal storage pathology in neurons. We investigated the effect of mutant CHMP2B on synaptic pathology, as ESCRT function was recently implicated in the degradation of synaptic vesicle (SV) proteins. We report here that expression of C-terminally truncated mutant CHMP2B results in a novel synaptopathy. This unique synaptic pathology is characterised by selective retention of presynaptic SV trafficking proteins in aged mutant CHMP2B transgenic mice, despite significant loss of postsynaptic proteins. Furthermore, ultrastructural analysis of primary cortical cultures from transgenic CHMP2B mice revealed a significant increase in the number of presynaptic endosomes, while neurons expressing mutant CHMP2B display defective SV recycling and alterations to functional SV pools. Therefore, we reveal how mutations in CHMP2B affect specific presynaptic proteins and SV recycling, identifying CHMP2B FTD as a novel synaptopathy. This novel synaptopathic mechanism of impaired SV physiology may be a key early event in multiple forms of FTD, since proteins that mediate the most common genetic forms of FTD all localise at the presynapse.
CHMP2B 是 ESCRT-III 亚基中的一个突变可导致额颞叶痴呆（FTD），并导致神经元内的内溶酶体运输和溶酶体储存病变受损。我们研究了突变 CHMP2B 对突触病变的影响，因为最近 ESCRT 功能被牵连到突触小泡（SV）蛋白的降解中。我们在这里报告，表达 C 端截断的突变 CHMP2B 会导致一种新的突触病。这种独特的突触病变的特征是，尽管突触后蛋白明显丢失，但在老年突变 CHMP2B 转基因小鼠中，突触前 SV 运输蛋白仍被选择性保留。此外，对来自转基因 CHMP2B 小鼠的原代皮质培养物的超微结构分析显示，突触前内体的数量显著增加，而表达突变 CHMP2B 的神经元显示 SV 循环功能缺陷和功能性 SV 池的改变。因此，我们揭示了 CHMP2B 突变如何影响特定的突触前蛋白和 SV 循环，将 CHMP2B FTD 确定为一种新的突触病。这种 SV 生理学受损的新型突触病机制可能是多种形式的 FTD 的一个关键早期事件，因为介导最常见的 FTD 遗传形式的蛋白质都定位于突触前。
