A novel synaptopathy-defective synaptic vesicle protein trafficking in the mutant CHMP2B mouse model of frontotemporal dementia
A novel synaptopathy-defective synaptic vesicle protein trafficking in the mutant CHMP2B mouse model of frontotemporal dementia
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DOI：
10.1111/jnc.15551
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发表时间：
2021-12-11
影响因子：
4.7
通讯作者：
Schorge, Stephanie
中科院分区：
文献类型：
--
作者：
Clayton, Emma L.;Bonnycastle, Katherine;Schorge, Stephanie
ESCRT-III亚基CHMP 2B的突变导致额颞叶痴呆（FTD），并导致神经元内溶酶体运输受损和溶酶体储存病理学。我们研究了突变体CHMP 2B对突触病理学的影响，因为ESCRT功能最近与突触囊泡（SV）蛋白的降解有关。我们在这里报告的C-末端截短突变CHMP 2B的表达结果在一个新的突触病。这种独特的突触病理学的特点是选择性保留突触前SV运输蛋白在老年突变CHMP 2B转基因小鼠，尽管突触后蛋白的显着损失。此外，从转基因CHMP 2B小鼠的原代皮层培养物的超微结构分析显示突触前内体的数量显着增加，而表达突变CHMP 2B的神经元显示缺陷SV回收和功能SV池的改变。因此，我们揭示了CHMP 2B突变如何影响特定的突触前蛋白和SV再循环，将CHMP 2B FTD确定为一种新型突触病。SV生理功能受损的这种新型突触病变机制可能是多种形式FTD的关键早期事件，因为介导最常见遗传形式FTD的蛋白质均定位于突触前。
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.