Researchers have discovered a mechanism that may explain how a recently discovered mutation causes two devastating neurological diseases.
The findings offer an insight into the biology associated with the C9orf72 mutation as well as identifying a potential path for the development of therapy, says Margaret Sutherland, program director at the National Institute of Neurological Disorders and Stroke.
A mutation in the C9orf72 gene was first linked to the development of amyotrophic lateral sclerosis (ALS) and of frontotemporal dementia (FTD) two years ago.
Also known as motor neurone disease, ALS is a debilitating condition caused by degeneration of the nerves that control muscle movement. In FTD, the nerve cells that control our emotions, behaviour and language become damaged.
Now, researchers from the John Hopkins University School of Medicine report that among people who have the mutation, abnormalities in the RNA molecules that carry genetic instructions may be at the root of both diseases.
After analyzing the behaviour of DNA and RNA affected by the mutation, Jiou Wang and colleagues found that both form abnormal structures called G-quadruplexes.
These quadruplexes look rather like a stack of shelves and are formed when guanines, that are present in the repeats of a certain nucleotide sequence, link up and stick together.
The researchers also found that the RNA forms other abnormal shapes that together with the G-quadruplexes may prevent the normal function of nucleic acid.
Furthermore, the team reports that new RNA strands based on the mutated gene often fail to complete and instead populate the cell nucleus with pieces of dysfunctional RNA.
This “bad” RNA was found to bind to 288 proteins, which became stuck and unable to perform their usual roles.
The team says that although the findings suggest that the clumping of abnormal RNA molecules seems to be key to the pathology of ALS and FDL, it is still possible that the gene’s protein product plays a role.
“It could be simultaneous,” explains Wang… “bad RNA accumulating, plus you're losing some of the protein itself.”
However, the study has shed light on how this gene effects RNA as well as the protein involved in the disease, he says.