التفاصيل البيبلوغرافية
| العنوان: |
DNA repair in Huntington's disease: investigating somatic instability mechanisms and therapeutic targeting of MSH3 |
| المؤلفون: |
Bunting, Emma Lucia |
| المساهمون: |
Tabrizi, Sarah, Flower, Michael, Plun-Favreau, Helen |
| المصدر: |
Doctoral thesis, UCL (University College London). |
| بيانات النشر: |
UCL (University College London) |
| سنة النشر: |
2024 |
| المجموعة: |
University College London: UCL Discovery |
| مصطلحات موضوعية: |
Huntington's disease, MSH3, somatic instability, somatic expansion, CAG repeat expansion, CAG repeat instability, repeat expansion disorders, DNA repair, Mismatch repair |
| الوصف: |
Huntington’s disease is a fatal neurodegenerative condition caused by a CAG repeat expansion mutation in the huntingtin gene. Repeat tracts are susceptible to somatic instability through strand misalignment and formation of mutagenic slip-out structures, the erroneous repair of which leads to a change in the number of repeat units. Although both expansions and contractions of the repeat tract can occur, there is an overall bias towards expansion events, leading to somatic expansion throughout an individual’s life which drives the progression of the disease. Recent genome-wide association studies have converged on DNA repair loci as modifiers of disease phenotype, with decades of previous work in animal and cell models to suggest they exert their effects by influencing somatic instability. The leading SNP of the TRACK-HD GWAS was recently shown to be driven by a 27 base-pair deletion variant in exon 1 of the mismatch repair gene, MSH3, termed ‘MSH3 3a’. This variant is associated with a delayed disease onset, slowed disease progression, and reduced somatic expansion. Here, in vitro DNA repair assays performed with functional extracts from TRACK-HD patient-derived lymphoblastoid lines suggest this variant exerts its protective effects through functional differences, which are dependent on protein expression above a certain threshold. Additionally, exploratory analyses highlight differences in slip-out repair of other modifying variants, including PMS1 rs3791767 and LIG1 rs274883. The effects of MSH3 lowering in 125 CAG HD patient iPSC-derived neurons was also explored using an antisense oligonucleotide developed by IONIS. MSH3 lowering resulted in a dose-dependent effect on somatic instability, with 50% being sufficient to significantly slow somatic expansion, and 75% lowering predicted to completely ablate it. These data collectively provide mechanistic insight into Huntington’s disease pathogenesis and highlight the therapeutic potential of MSH3 lowering. |
| نوع الوثيقة: |
doctoral or postdoctoral thesis |
| اللغة: |
English |
| العلاقة: |
https://discovery.ucl.ac.uk/id/eprint/10185273Test/ |
| الإتاحة: |
https://discovery.ucl.ac.uk/id/eprint/10185273Test/ |
| رقم الانضمام: |
edsbas.47E3CCEE |
| قاعدة البيانات: |
BASE |
