The discovery of triplet stabilizing factors brings hope to Huntington's disease and other repetitive expansion disorders

When CAG nucleotide triplets are overrepeated in a gene called Huntington, a devastating, currently untreatable neurodegenerative "repetitive expansion disorder" appears, called Huntington's disease (HD)
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The latest study by a research team from University College London (UCL) and the University of Cambridge has found that a mechanism in the DNA "mismatch repair" pathway can prevent abnormal trinucleotide repeat amplification, thereby preventing the progression of HD
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These findings may lead to new treatments for HD and other rare repetitive diseases
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The article was published in Cell Reports, “FAN1 controls the assembly of mismatch repair complexes through MLH1 retention to stabilize CAG repeat expansion in Huntington’s disease

A recent genome-wide association study (GWAS) has determined that FAN1 is a modifier of Huntington's disease-a gene that changes the expression of disease symptoms

Through research designed in human cells and a program that can read and count CAG repeats, the researchers established FAN1 to stop repeat amplification by blocking the accumulation of DNA mismatch repair protein complexes, thereby reducing the toxicity of patient-derived cells
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The author points out: "In this study, we investigated the interaction of HD gene modifiers FAN1 and MLH1, and their role in repeated instability in patient-derived cells, HD mouse models, and U2OS cell systems
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"

Through biochemical co-immunoprecipitation analysis, the authors proved that FAN1 competes with the DNA mismatch repair protein MSH3 and physically interacts with MLH1, another member of the DNA mismatch repair pathway, thereby inhibiting the assembly of the functional mismatch repair protein complex.
Promote CAG repeat expansion
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The researchers also identified a specific conservative base model at the amino terminus of FAN1, called the SPYF base model, which binds to MLH1

The authors found that FAN1 stabilizes CAG repeats in two different ways
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On the one hand, it binds to MLH1 and restricts its binding to MSH3, thereby inhibiting the assembly of functional mismatch repair complexes.

Robert Goold and Joseph Hamilton, co-authors from the Queen’s Square Neurology Institute at University College London and the British Dementia Institute, said: “Over the years, evidence that DNA repair genes alter Huntington’s disease has been increasing
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We show that new mechanisms are still waiting.
I found that this is good news for patients

The team is currently working with Adrestia Therapeutics, a biotechnology company located in the Babraham Research Park near Cambridge, to translate these findings into treatments for a large number of patients in the UK and around the world

Dr.
Sarah Tabrizi is the director of the Huntington’s Disease Centre at University College London, the Queen’s Square Neurology Institute at University College London, and the Dementia Institute at University College London.
The importance of the model and check whether it is therapeutically controllable
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We are now working with key pharmaceutical partners to try to develop therapies for this mechanism, which may one day enter the clinic

Dr.
Gabriel Balmus from the British Dementia Institute at the University of Cambridge is the co-corresponding author of this paper.
He said: “There are currently more than 50 CAG repeat expansion disorders that are incurable
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If feasible, this field shows that The resulting treatment can be applied not only to Huntington’s disease, but also to all other repeat expansion disorders