An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains unclear. Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS. We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduced C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors, leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion. Thus, cooperativity between gain- and loss-of-function mechanisms led to neurodegeneration. Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescued patient neuron survival and ameliorated neurodegenerative processes in both gain- and loss-of-function C9ORF72 mouse models. Thus, modulating vesicle trafficking was able to rescue neurodegeneration caused by the C9ORF72 repeat expansion. Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS and FTD.

中文翻译：

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单倍体不足会导致 C9ORF72 ALS/FTD 人类诱导的运动神经元的神经变性。


C9ORF72 中的内含子 GGGGCC 重复序列扩展是肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 的最常见原因，但该重复序列的致病机制仍不清楚。使用人类诱导运动神经元 (iMN)，我们发现重复扩增的 C9ORF72 在 ALS 中单倍体不足。我们发现 C9ORF72 与内体相互作用，并且是运动神经元中正常囊泡运输和溶酶体生物发生所必需的。重复扩增降低了 C9ORF72 的表达，通过两种机制引发神经变性：谷氨酸受体的积累，导致兴奋性毒性，以及重复扩增衍生的神经毒性二肽重复蛋白的清除受损。因此，功能获得和功能丧失机制之间的协同作用导致神经变性。在功能获得和功能丧失的 C9ORF72 小鼠模型中，恢复 C9ORF72 水平或用组成型活性 RAB5 或 RAB5 效应器的化学调节剂增强其功能可挽救患者神经元存活并改善神经退行性过程。因此，调节囊泡运输能够挽救由 C9ORF72 重复扩增引起的神经变性。结合 ALS2、FIG4、CHMP2B、OPTN 和 SQSTM1 的罕见突变，我们的结果揭示了 ALS 和 FTD 中囊泡运输的机制趋同。