Synaptic dysfunction induced by glycine-alanine dipeptides in C9orf72-ALS/FTD is rescued by SV2 replenishment
Synaptic dysfunction induced by glycine-alanine dipeptides in C9orf72-ALS/FTD is rescued by SV2 replenishment
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DOI：
10.15252/emmm.201910722
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发表时间：
2020-04-29
影响因子：
11.1
通讯作者：
Trotti, Davide
中科院分区：
文献类型：
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作者：
Jensen, Brigid K.;Schuldi, Martin H.;Trotti, Davide
肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的最常见原因是C9 orf 72基因中的内含子六核苷酸重复扩增。在疾病中，含有该扩展区域的RNA转录物经历重复相关的非AUG翻译以产生二肽重复蛋白（DPR），其在患者的脑和脊髓中被检测到，并且在体外和体内范例中都具有神经毒性。我们在此揭示了ALS/FTD尸检组织中最大量检测到的DPR的一种新的致病机制，即聚甘氨酸丙氨酸（GA）。以前，我们在GA小鼠模型中显示了运动功能障碍，而没有运动神经元的损失。在这里，我们证明了移动的GA聚集体存在于神经突内，引起突触囊泡相关蛋白2（SV 2）的减少，并改变Ca 2+内流和突触囊泡释放。这些表型可以通过恢复SV 2水平来纠正。在GA小鼠中，观察到SV 2的丢失，而运动神经元数量没有减少。值得注意的是，在源自患者诱导的多能干细胞系的皮质和运动神经元中观察到SV 2的减少，表明突触改变也发生在患者中。
The most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an intronic hexanucleotide repeat expansion in the C9orf72 gene. In disease, RNA transcripts containing this expanded region undergo repeat-associated non-AUG translation to produce dipeptide repeat proteins (DPRs), which are detected in brain and spinal cord of patients and are neurotoxic both in vitro and in vivo paradigms. We reveal here a novel pathogenic mechanism for the most abundantly detected DPR in ALS/FTD autopsy tissues, poly-glycine-alanine (GA). Previously, we showed motor dysfunction in a GA mouse model without loss of motor neurons. Here, we demonstrate that mobile GA aggregates are present within neurites, evoke a reduction in synaptic vesicle-associated protein 2 (SV2), and alter Ca2+ influx and synaptic vesicle release. These phenotypes could be corrected by restoring SV2 levels. In GA mice, loss of SV2 was observed without reduction of motor neuron number. Notably, reduction in SV2 was seen in cortical and motor neurons derived from patient induced pluripotent stem cell lines, suggesting synaptic alterations also occur in patients.