title: C9orf72: At the intersection of lysosome cell biology and neurodegenerative disease.
abstract: The discovery that expansion of a hexanucleotide repeat within a noncoding region of the C9orf72 gene causes amyotrophic lateral sclerosis and frontotemporal dementia raised questions about C9orf72 protein function and potential disease relevance. The major predicted structural feature of the C9orf72 protein is a DENN (differentially expressed in normal and neoplastic cells) domain. As DENN domains are best characterized for regulation of specific Rab GTPases, it has been proposed that C9orf72 may also act through regulation of a GTPase target. Recent genetic and cell biological studies furthermore indicate that the C9orf72 protein functions at lysosomes as part of a larger complex that also contains the Smith-Magenis chromosome region 8 (SMCR8) and WD repeat-containing protein 41 (WDR41) proteins. An important role for C9orf72 at lysosomes is supported by defects in lysosome morphology and mTOR complex 1 (mTORC1) signaling arising from C9orf72 KO in diverse model systems. Collectively, these new findings define a C9orf72-containing protein complex and a lysosomal site of action as central to C9orf72 function and provide a foundation for the elucidation of direct physiological targets for C9orf72. Further elucidation of mechanisms whereby C9orf72 regulates lysosome function will help to determine how the reductions in C9orf72 expression levels that accompany hexanucleotide repeat expansions contribute to disease pathology.
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut.|Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Joseph
authors.initials: J
authors.lastname: Amick
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut.|Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Ferguson
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D000818:Animals; D057180:Frontotemporal Dementia / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology*; D011506:Proteins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D020691:rab GTP-Binding Proteins
chemical_list: D011506:Proteins; D058570:TOR Serine-Threonine Kinases; D020691:rab GTP-Binding Proteins
keywords: Birt-Hogg-Dubé syndrome; C9orf72; FLCN; SMCR8; amyotrophic lateral sclerosis; autophagy; frontotemporal dementia; lysosome; mTORC1; neurodegeneration