C9orf72: At the intersection of lysosome cell biology and neurodegenerative disease. (23rd March 2017)

• Record Type: Journal Article
• Authors: Amick, Joseph; Ferguson, Shawn M.
• Is Part Of: Traffic. Volume 18:Number 5(2017)
• Page Start: 267
• Page End: 276
• Publication Date: 2017-03-23
• Subjects: amyotrophic lateral sclerosis -- autophagy -- Birt‐Hogg‐Dubé syndrome -- C9orf72 -- FLCN -- frontotemporal dementia -- lysosome -- mTORC1 -- neurodegeneration -- SMCR8; Biological transport -- Periodicals; 571.6
• DOI: 10.1111/tra.12477
• Languages: English
• ISSNs: 1398-9219

Abstract

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. Abstract : 3 distinct mechanisms that have been proposed to explain how hexanucleotide repeat expansion within the C9orf72 gene causes neurodegeneration. (1) RNAs transcribed from the hexanucleotide repeat expansion form nuclear foci, which may trap key proteins involved in RNA processing. (2) Dipeptide repeat proteins produced by repeat associated non‐AUG (RAN) translation form aggregates that may impair the function of membraneless organelles such as nucleoli and stress granules. Dipeptide repeat proteins may also disrupt transport through nuclear pores. (3) The repeat expansion also suppresses expression of the endogenous C9orf72 protein. Based on recent knockout studies, loss of C9orf72 is predicted to impair lysosome function This review focuses on recent progress toward elucidating lysosome‐related functions for C9orf72.