SIL1 in human familial and sporadic amyotrophic lateral sclerosis (ALS)

肌萎缩侧索硬化症(ALS)的病理特征是错误折叠蛋白的异常堆积，导致内质网(ER)应激。内质网共伴侣SIL1的突变导致Marinesco-Sjögren综合征(MSS；小脑变性、白内障和空泡性肌病)。最近我们和其他人的研究表明，SIL1突变导致患者和小鼠特异性的ER改变，SIL1调节SOD1ALS小鼠运动神经元(MN)亚型选择性ER应激。我们的项目是为了进一步明确sIL-1如何参与α-MN的生存和维持。我们假设，SIL1保护MNS免受内质网应激、自噬受损和错误折叠的FUS、TDP-43和其他与ALS发病相关的RNA结合蛋白的异常堆积。我们的初步结果表明，sIL-1及其结合伙伴GRP78与抗病的人α-MN的尼氏物质结合，并且sIL-1经常与人ALS中异常的神经元内聚集共存。我们将使用大量家族性和散发性肌萎缩侧索硬化症病例、肌萎缩侧索硬化症患者IPSC来源的MN和其他细胞培养系统以及小鼠模型(FUS-ALS和缺乏sIL-1的小鼠)的尸检样本来检验以下假设：(A)在人类家族性和散发性肌萎缩侧索硬化症中存在与sIL-1表达相关的α-MN亚型特异性易损性。(B)SIL1参与了异常蛋白质聚集体的去除。(C)SIL1以与ALS病理相关的方式调节内质网(ER吞噬)和部分核(吞核)的巨型自噬和/或选择性自噬，以控制蛋白质质量。这些翻译研究将深入了解蛋白代谢异常和内质网病理在人类MN变性中的作用，以及SIL1在ALS中的保护作用。

Abnormal accumulations of misfolded proteins that elicit endoplasmic reticulum (ER) stress are pathological hallmarks of amyotrophic lateral sclerosis (ALS). Mutation of the ER co-chaperon SIL1 causes Marinesco-Sjögren syndrome (MSS; cerebellar degeneration, cataracts and vacuolar myopathy). Recent studies by us and others showed that SIL1 mutation leads to specific ER alterations in patients and mice and that SIL1 regulates motor neuron (MN) subtype-selective ER stress in SOD1 ALS mice. Our project is specifically designed to further define how SIL1 is implicated in survival and maintenance of α-MNs. We hypothesize that SIL1 protects MNs from damage elicited by ER stress, impaired autophagy and abnormal accumulation of misfolded FUS, TDP-43 and other RNA-binding proteins linked to ALS pathogenesis. Our preliminary results indicate that SIL1 and its binding partner GRP78 associate with the Nissl substance of disease-resistant human α-MNs and that SIL1 often co-localizes with abnormal intraneuronal aggregates in human ALS. We will use autopsy samples from a large cohort of familial and sporadic ALS cases, ALS patient ipSC-derived MNs and other cell culture systems as well as mouse models (FUS-ALS and woozy mice lacking SIL1) to test the following hypotheses: (A) There is α-MN subtype-specific vulnerability in human familial and sporadic ALS linked to SIL1 expression. (B) SIL1 is involved in the removal of abnormal protein aggregates. (C) SIL1 regulates macroautophagy and/or selective autophagy of the ER (ER-phagy) and of part of the nucleus (nucleophagy) for protein quality control in a way relevant for ALS pathology. These translational studies will provide insight into the contribution of abnormal proteostasis and of ER pathology to human MN degeneration and into the protective role of SIL1 in ALS.