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.

Keywords: Birt-Hogg-Dubé syndrome; C9orf72; FLCN; SMCR8; amyotrophic lateral sclerosis; autophagy; frontotemporal dementia; lysosome; mTORC1; neurodegeneration.

Figure 1. Parallels between C9orf72:SMCR8 and FLCN:FNIP complexes

A) Summary of the predicted domain organization of C9orf72, FNIP1, SMCR8 and C9orf72 that illustrates that the DENN domain represents the major folded element in each of these proteins. Also noted at the N-terminal region of each of these DENN domains is a region that has similarity to the Longin domain that is found in many GTPase regulating proteins. B) WDR41 is predicted to contain 8 WD40 repeats. C) Schematic diagram summarizing functions and lysosomal localization of the C9orf72:SMCR8:WDR41 and FLCN:FNIP complexes.