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

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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.