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dc.contributor.authorSullivan, Peter Mayo
dc.date.accessioned2018-04-26T14:18:17Z
dc.date.available2019-09-11T06:02:32Z
dc.date.issued2017-08-30
dc.identifier.otherSullivan_cornellgrad_0058F_10423
dc.identifier.otherhttp://dissertations.umi.com/cornellgrad:10423
dc.identifier.otherbibid: 10361680
dc.identifier.urihttps://hdl.handle.net/1813/57003
dc.description.abstractIntronic 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.
dc.language.isoen_US
dc.subjectALS
dc.subjectC9orf72
dc.subjectFTLD
dc.subjectLysosome
dc.subjectSMCR8
dc.subjectWDR41
dc.subjectCellular biology
dc.subjectMolecular biology
dc.titleElucidating the disease relevance and function of the ALS/FTLD-associated protein C9orf72
dc.typedissertation or thesis
thesis.degree.disciplineBiochemistry, Molecular and Cell Biology
thesis.degree.grantorCornell University
thesis.degree.levelDoctor of Philosophy
thesis.degree.namePh. D., Biochemistry, Molecular and Cell Biology
dc.contributor.chairHu, Fenghua
dc.contributor.committeeMemberQian, Shu-Bing
dc.contributor.committeeMemberEmr, Scott David
dcterms.licensehttps://hdl.handle.net/1813/59810
dc.identifier.doihttps://doi.org/10.7298/X4B56GWT


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