Summary: Researchers have identified the normal function of C9orf72, a gene commonly implicated in ALS and FTD.
Source: University of Bath.
The normal function of a gene associated with the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has been determined for the first time by University of Bath scientists.
Both ALS, the most common form of motor neurone disease, and FTD progressively develop in adults and have been shown to be closely linked, with overlapping genetic origins and similar effects on some nervous system cells. There is no cure for either disease.
One gene, called C9orf72, is strongly suspected to be the cause of inherited ALS and FTD when a short sequence of DNA repeats hundreds or even thousands of times within the gene, causing problems in its transcription and expression. However, until now scientists were uncertain as to what normal role or roles the C9orf72 gene played in cells.
A University of Bath team from the Department of Biology and Biochemistry have now biochemically characterised the protein produced by the C9orf72 gene and have shown that it is a guanine nucleotide exchange factor (GEF).
GEFs are a type of protein which regulate molecules called RABs which control key processes inside cells. They respond to signals received by a cell in normal as well as diseased states. Recent evidence suggests that some GEF proteins may be potential therapeutic targets for developing drugs to treat various diseases, including cancer.
The study is published in PeerJ — Life and Environment Journal.
Dr Vasanta Subramanian, who led the study alongside Professor K. Ravi Acharya, said: “It is vital that we know as much as we can about the causes and triggers for ALS and FTD, so we have a better chance of developing treatments, and even one day a cure for these devastating diseases.
“Understanding the function of C9orf72, which is linked to both diseases, is a crucial step in that process.”
Dr Brian Dickie, Director of Research at the Motor Neurone Disease Association, said: “These findings are very timely, as new gene therapy approaches are being developed to specifically target the C9orf72 gene. Understanding what the healthy gene is doing within cells will be important in ensuring that the toxic and not the beneficial effects of the gene are targeted.
Funding: This work was supported by a research grant from Motor Neurone Disease Association, UK.
Source: Chris Melvin – University of Bath
Publisher: Organized by NeuroscienceNews.com.
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Original Research: Open access research for “C9orf72, a protein associated with amyotrophic lateral sclerosis (ALS) is a guanine nucleotide exchange factor” by Shalini Iyer, Vasanta Subramanian, and K. Ravi Acharya in PeerJ. Published October 17 2018.
C9orf72, a protein associated with amyotrophic lateral sclerosis (ALS) is a guanine nucleotide exchange factor
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.