Elucidating the disease relevance and function of the ALS/FTLD-associated protein C9orf72

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Intronic hexanucleotide repeat expansion in the C9orf72 gene is a leading cause of frontotemporal lobar degeneration (FTLD) with amyotrophic lateral sclerosis (ALS). Among several hypotheses, reduced expression of C9orf72 has been proposed as a possible disease mechanism. However, the function of C9orf72 remains unclear. Here, I have presented data that begins to elucidate the function of C9orf72 at a cellular and organismal level. My data has found that C9orf72 binds SMCR8 and WDR41 to form a protein complex. Each component of this complex is important for the stability of the entire complex, as loss of any one of these three protein causes a decrease of other complex components. SMCR8 protein is almost completely lost in the C9orf72-/- mouse tissues, but has little change in the WDR41-/- mice, whereas C9orf72 levels are decreased by loss of either SMCR8 or WDR41. I have also shown that the C9orf72 complex interacts with the Ulk1-FIP200 complex, as well as the cytoskeletal component tubulin, and several Rab GTPases. Furthermore, I provide evidence that mTOR phosphorylation and localization is mis-regulated and that AKT phosphorylation is also altered in SMCR8-/- cells, leading to mis-regulated autophagy-lysosome functions. Finally, I have created knockout mice for C9orf72, SMCR8, and WDR41 using CRISPR-Cas9 and preliminarily characterized the phenotypes that these mice exhibit. Altogether, my data support a role for the C9orf72-SMCR8-WDR41 complex in regulating the autophagy-lysosome pathway and maintaining proper immune regulation.

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ALS; C9orf72; FTLD; Lysosome; SMCR8; WDR41; Cellular biology; Molecular biology


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Union Local


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Hu, Fenghua

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Qian, Shu-Bing
Emr, Scott David

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Biochemistry, Molecular and Cell Biology

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Ph. D., Biochemistry, Molecular and Cell Biology

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Doctor of Philosophy

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Government Document




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dissertation or thesis

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