When CAG nucleotide triplets repeat excessively in a gene called huntingtin, a devastating and currently untreatable neurodegenerative “repeat expansion disorder” arises called Huntington’s Disease (HD).
New research from groups at the University College of London (UCL) and the University of Cambridge has identified a mechanism in the DNA ‘mismatch repair’ pathway that stops the abnormal trinucleotide repeat expansion and thereby the progression of HD.
These findings that could result in new therapies for HD and other rare repeat expansion disorders are published in the Cell Reports article, “FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington’s disease.”
Recent genome-wide association studies (GWAS) have identified FAN1 as a modifier of Huntington’s disease—a gene that modifies the expression of the disease symptoms. In this study researchers investigate the role of FAN1, a DNA repair nuclease of the Fanconi anemia pathway.
Through studies designed in human cells and protocols that can read and count CAG repeats, the researchers establish FAN1 stops repeat expansion by blocking the accumulation of the DNA mismatch repair protein complexes, thus alleviating toxicity in patient-derived cells.
The authors note, “In this study, we investigated the interaction of the HD genetic modifiers FAN1 and MLH1 and their role in repeat instability in patient-derived cells, HD mouse models, and a U2OS cell system.”
Through biochemical co-immunoprecipitation assays, the authors demonstrate FAN1 competes with MSH3, a DNA mismatch repair protein, to physically interact with MLH1, another member of the DNA mismatch repair pathway, thereby inhibiting the assembly of a functional mismatch repair protein complex that would otherwise promote CAG repeat expansion. The researchers also identify a specific conserved motif, called an SPYF motif, at the amino terminus of FAN1 that binds to MLH1.
The authors show FAN1 stabilizes CAG repeats through two distinct routes. On one hand, it binds MLH1 to restrict its binding to MSH3, thus inhibiting the assembly of a functional mismatch repair complex, and on the other hand, its nuclease activity promotes accurate repair. This pivotal role of FAN1 highlights a potential avenue for HD therapeutics. Pharmaceutically mimicking or enhancing FAN1 mediated blocking of mismatch repair would alter the course of the disease.
Co-lead authors Robert Goold, PhD, and Joseph Hamilton, PhD, both from UCL Queen Square Institute of Neurology and U.K. Dementia Research Institute at UCL, say: “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.”
The team is now working with the biotechnology company Adrestia Therapeutics, based at the Babraham Research Campus near Cambridge, to translate these discoveries into therapies for substantial numbers of patients in the U.K. and worldwide.
Sarah Tabrizi, PhD, director of the UCL Huntington’s Disease Centre, UCL Queen Square Institute of Neurology and U.K. Dementia Research Institute at UCL, says “Our next step is to determine how important this interaction is in more physiological models and examine if it is therapeutically tractable. We are now working with key pharma partners to try and develop therapies that target this mechanism and might one day reach the clinic.” Tabrizi is senior author of the study.
Gabriel Balmus, PhD, co-senior author of the paper from the U.K. Dementia Research Institute at the University of Cambridge, says, “There are currently more than fifty CAG repeat expansion disorders that are incurable. If viable, the field suggests that resulting therapies could be applied not only to Huntington’s disease but to all the other repeat expansion disorders.”
Steve Jackson, FRS FMedSci, CSO and Interim CEO at Adrestia, says, “My colleagues and I are delighted to be working with Professor Tabrizi, Dr Balmus and the U.K. Dementia Research Institute to seek ways to translate their exciting science towards new medicines for Huntington’s disease and potentially also other DNA-repeat expansion disorders.”