A C9orf72 ALS/FTD Ortholog Acts in Endolysosomal Degradation and Lysosomal Homeostasis
A C9orf72 ALS/FTD Ortholog Acts in Endolysosomal Degradation and Lysosomal Homeostasis
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DOI：
10.1016/j.cub.2018.03.063
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发表时间：
2018-05-21
期刊：
影响因子：
9.2
通讯作者：
Horvitz, H. Robert
中科院分区：
文献类型：
--
作者：
Corrionero, Anna;Horvitz, H. Robert
肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 最常见的遗传原因是基因 C9orf72 的非编码区中六核苷酸重复的扩展。我们报告，C9orf72 的秀丽隐杆线虫直系同源物 alfa-1 的功能丧失突变导致一种新的表型缺陷：内吞卵黄异常释放到胚胎外空间，导致折射“斑点”。人类 C9orf72 蛋白的表达部分挽救了 alfa-1 斑点表型，这表明 C9orf72 和alfa-1 具有类似的功能，我们通过对具有 blob 表型的突变体进行遗传筛选，将其重命名为 smcr-8，其作用在内溶酶体内容物的降解和随后的溶酶体重组中。溶酶体重组中的 alfa-1 异常导致溶酶体稳态的普遍失调，导致吞噬体和自噬体内容物的降解缺陷。我们认为，与 alfa-1 一样，C9orf72 在内吞物质的降解和溶酶体稳态的维持中发挥作用，C9orf72 的这种先前未描述的功能解释了有关 C9orf72 及其同源物突变影响的各种不同观察结果，包括溶酶体的异常积累和溶酶体与吞噬体的融合缺陷。 C9orf72 突变引起的 ALS/FTD，例如免疫反应改变、自噬靶标聚集和神经元过度兴奋，是由于 C9orf72 基因功能降低以及随后的溶酶体降解异常造成的。
The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the expansion of a hexanucleotide repeat in a non-coding region of the gene C9orf72. We report that loss-of-function mutations in alfa-1, the Caenorhabditis elegans ortholog of C9orf72, cause a novel phenotypic defect: endocytosed yolk is abnormally released into the extra-embryonic space, resulting in refractile "blobs.'' The alfa-1 blob phenotype is partially rescued by the expression of the human C9orf72 protein, demonstrating that C9orf72 and alfa-1 function similarly. We show that alfa-1 and R144.5, which we identified from a genetic screen for mutants with the blob phenotype and renamed smcr-8, act in the degradation of endolysosomal content and subsequent lysosome reformation. The alfa-1 abnormality in lysosomal reformation results in a general dysregulation in lysosomal homeostasis, leading to defective degradation of phagosomal and autophagosomal contents. We suggest that, like alfa-1, C9orf72 functions in the degradation of endocytosed material and in the maintenance of lysosomal homeostasis. This previously undescribed function of C9orf72 explains a variety of disparate observations concerning the effects of mutations in C9orf72 and its homologs, including the abnormal accumulation of lysosomes and defective fusion of lysosomes to phagosomes. We suggest that aspects of the pathogenic and clinical features of ALS/FTD caused by C9orf72 mutations, such as altered immune responses, aggregation of autophagy targets, and excessive neuronal excitation, result from a reduction in C9orf72 gene function and consequent abnormalities in lysosomal degradation.