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

引起内质网（ER）应激的错误折叠蛋白的异常积累是肌萎缩侧索硬化症（ALS）的病理标志。内质网共同伴侣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）。我们等人最近的研究表明，SIL1突变导致患者和小鼠特异性内质网改变，并且SIL1调节SOD1 ALS小鼠运动神经元（MN）亚型选择性内质网应激。我们的项目是专门设计来进一步确定SIL1如何与α-MNs的生存和维持有关。我们假设SIL1保护MNs免受内质网应激、自噬受损以及错误折叠的FUS、TDP-43和其他与ALS发病机制相关的rna结合蛋白的异常积累所引起的损伤。我们的初步结果表明，SIL1及其结合伙伴GRP78与人类抗病α-MNs的Nissl物质相关，并且SIL1经常与人类ALS中异常的神经元内聚集体共定位。我们将使用来自家族性和散发性ALS病例、ALS患者ipsc衍生的MNs和其他细胞培养系统以及小鼠模型（FUS-ALS和缺乏SIL1的woozy小鼠）的尸检样本来验证以下假设：(a)人类家族性和散发性ALS中存在与SIL1表达相关的α-MN亚型特异性易感性。(B) SIL1参与异常蛋白聚集体的去除。(C) SIL1调节内质网的巨噬和/或选择性自噬（ER-phagy）和部分细胞核的自噬（nucleophagy），以控制蛋白质质量，与ALS病理相关。这些转化研究将有助于深入了解异常蛋白酶和ER病理在人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.