C9orf72, a protein associated with amyotrophic lateral sclerosis (ALS) is a guanine nucleotide exchange factor

• Published in: PeerJ (San Francisco, CA) Vol. 6; p. e5815
• Main Authors: Iyer, Shalini, Subramanian, Vasanta, Acharya, K Ravi
• Format: Journal Article
• Language: English
• Published: United States PeerJ. Ltd 17.10.2018; PeerJ, Inc; PeerJ Inc
• Subjects: Amino acids; Amyotrophic lateral sclerosis; Autophagy; Binding proteins; Biochemistry; Biophysics; C9orf72; Cloning; Cytoskeleton; Dementia; Dementia disorders; Deoxyribonucleic acid; DNA; Endocytosis; Frontotemporal dementia; Gene expression; Genetic aspects; Guanine; Guanine nucleotide exchange factor; Guanine nucleotide-binding protein; Guanosine triphosphatases; Molecular Biology; Mutation; Neurodegenerative diseases; Phagocytosis; Plasmids; Protein expression; Protein purification; Protein transport; Proteins; Rab GTPases; Rapamycin; Signal transduction; Size-exclusion chromatography; TOR protein; United States > US; Neurodegeneration; Protein purification; Rab GTPases; ALS; Protein expression; Size-exclusion chromatography; Guanine nucleotide exchange factor; C9orf72
• ISSN: 2167-8359; 2167-8359
• DOI: 10.7717/peerj.5815

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two late onset neurodegenerative diseases, have been shown to share overlapping cellular pathologies and genetic origins. Studies suggest that a hexanucleotide repeat expansion in the first intron of the C9orf72 gene is the most common cause of familial FTD and ALS pathology. The C9orf72 protein is predicted to be a differentially expressed in normal and neoplastic cells domain protein implying that C9orf72 functions as a guanine nucleotide exchange factor (GEF) to regulate specific Rab GTPases. Reported studies thus far point to a putative role for C9orf72 in lysosome biogenesis, vesicular trafficking, autophagy and mechanistic target of rapamycin complex1 (mTORC1) signaling. Here we report the expression, purification and biochemical characterization of C9orf72 protein. We conclusively show that C9orf72 is a GEF. The distinctive presence of both Rab- and Rho-GTPase GEF activities suggests that C9orf72 may function as a dual exchange factor coupling physiological functions such as cytoskeleton modulation and autophagy with endocytosis.