Huntington’s disease (HD) affects around 1 in every 10,000 people in the UK. There is currently no cure for HD and no way to slow down or stop the brain changes that occur. In a recent study, researchers have found a new mechanism that may halt the progression of this devastating condition.
What is Huntington’s disease?
Huntington’s disease (HD) is a progressive neurodegenerative disorder that causes changes to the brain, which ultimately alter a patient’s movement, mood, and cognitive ability. These changes are caused by an increase in toxic repetitive nucleotide sequences in the huntingtin gene (HTT). The repetition of CAG sequences increases over time due to the malfunction of cellular machinery that promotes DNA repair. This phenomenon is known as DNA mismatch repair. The overuse of DNA mismatch repair drives the onset and progression of HD.
Searching for a mechanism that will halt Huntington’s disease progression
Previous studies have identified several DNA repair genes that act as modifiers of HD. For example, variants in the DNA repair genes, FAN1 and MHL1, have been identified in patients with HD. However, the relationship between the two proteins has not yet been established. In a recent study, published in Cell Reports, a team of researchers from UCL and the University of Cambridge, as a part of their research at the UK Dementia Research Institute, investigated the relationship between MHL1 and FAN1.
The researchers used human cells and mouse models to investigate the interaction between the HD modifiers MHL1 and FAN1. The results showed that FAN1 binds to MHL1 to block the accumulation of protein after DNA mismatch repair and protect against CAG repeat expansion. This process in turn can alleviate the toxicity that is found in the cells of patients with HD.
“Evidence for DNA repair genes modifying Huntington’s disease has been mounting for years. We show that new mechanisms are still waiting to be discovered, which is good news for patients.” said lead author Dr Robert Goold, UCL Queen Square Institute of Neurology and UK Dementia Research Institute at UCL.
Future applications
The team are currently working with pharmaceutical partners to investigate the importance of the relationship between FAN1 and MHL1 and whether this interaction could become a possible drug target for HD.
There are currently more than 50 repeat expansion disorders that have no cure. If this study is viable, it could lead to an investigation that could find a new therapy to either cure or slow down the progression of HD. This would be life-changing for not only those with HD but all those with repeat expansion disorders.
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