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dc.contributor.authorCorrionero Saiz, Ana
dc.contributor.authorHorvitz, Howard Robert
dc.date.accessioned2020-07-20T21:03:15Z
dc.date.available2020-07-20T21:03:15Z
dc.date.issued2018-05
dc.date.submitted2018-02
dc.identifier.issn0960-9822
dc.identifier.urihttps://hdl.handle.net/1721.1/126268
dc.description.abstractThe most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the expansion of a hexanucleotide repeat in a non-coding region of the gene C9orf72. We report that loss-of-function mutations in alfa-1, the Caenorhabditis elegans ortholog of C9orf72, cause a novel phenotypic defect: endocytosed yolk is abnormally released into the extra-embryonic space, resulting in refractile “blobs.” The alfa-1 blob phenotype is partially rescued by the expression of the human C9orf72 protein, demonstrating that C9orf72 and alfa-1 function similarly. We show that alfa-1 and R144.5, which we identified from a genetic screen for mutants with the blob phenotype and renamed smcr-8, act in the degradation of endolysosomal content and subsequent lysosome reformation. The alfa-1 abnormality in lysosomal reformation results in a general dysregulation in lysosomal homeostasis, leading to defective degradation of phagosomal and autophagosomal contents. We suggest that, like alfa-1, C9orf72 functions in the degradation of endocytosed material and in the maintenance of lysosomal homeostasis. This previously undescribed function of C9orf72 explains a variety of disparate observations concerning the effects of mutations in C9orf72 and its homologs, including the abnormal accumulation of lysosomes and defective fusion of lysosomes to phagosomes. We suggest that aspects of the pathogenic and clinical features of ALS/FTD caused by C9orf72 mutations, such as altered immune responses, aggregation of autophagy targets, and excessive neuronal excitation, result from a reduction in C9orf72 gene function and consequent abnormalities in lysosomal degradation. Corrionero and Horvitz show that the C. elegans gene alfa-1 functions in the degradation of endocytosed material and hence has effects on subsequent lysosomal reformation and lysosomal homeostasis maintenance. Human C9orf72 functions similarly. Aspects of ALS/FTD might result from decreased C9orf72 function and defective lysosomal degradation.en_US
dc.language.isoen
dc.publisherElsevier BVen_US
dc.relation.isversionofhttp://dx.doi.org/10.1016/j.cub.2018.03.063en_US
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivs Licenseen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.sourceAnna Corrioneroen_US
dc.titleA C9orf72 ALS/FTD Ortholog Acts in Endolysosomal Degradation and Lysosomal Homeostasisen_US
dc.typeArticleen_US
dc.identifier.citationCorrionero, Anna and H. Robert Horvitz. "A C9orf72 ALS/FTD Ortholog Acts in Endolysosomal Degradation and Lysosomal Homeostasis." Current Biology 28, 10 (May 2018): P1522-1535.e5 © 2018 Elsevier Ltden_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentMcGovern Institute for Brain Research at MITen_US
dc.relation.journalCurrent Biologyen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2020-07-17T13:50:22Z
dspace.date.submission2020-07-17T13:50:41Z
mit.journal.volume28en_US
mit.journal.issue10en_US
mit.licensePUBLISHER_CC
mit.metadata.statusComplete


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