Molecular mechanisms of triplet repeat instability in Huntington's disease

亨廷顿病三联体重复不稳定性的分子机制

• 批准号: 10441533
• 负责人: Anna Pluciennik
• 金额: $ 39万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441533
• 关键词: Address; Affect; Age; Age of Onset; Animal Model; Attenuated; Binding Proteins; Biochemical; Brain region; CAG repeat; Cells; Cerebellum; Consensus; Corpus striatum structure; DNA; DNA Interstrand Cross-Link Repair; DNA Interstrand Crosslinking; DNA Repair; DNA Repair Pathway; Disease; Equilibrium; Excision; Fragile X Syndrome; Genes; Genetic; Genome Stability; Goals; Human; Huntington Disease; Huntington gene; Individual; Inherited; Knock-in Mouse; Knock-out; Length; Light; MLH1 gene; MSH2 gene; MSH3 gene; Maps; Mismatch Repair; Mismatch Repair Gene Inactivation; Molecular; Mus; Myotonic dystrophy type 1; Neurodegenerative Disorders; Neurons; Onset of illness; Outcome; PMS1 gene; PMS2 gene; Pathway interactions; Patients; Phenotype; Process; Proteins; Proteomics; Regulation; Role; Somatic Cell; System; Testing; Therapeutic Intervention; Tissues; Trinucleotide Repeats; age related; causal variant; cell type; gene repair; genome wide association study; induced pluripotent stem cell; insight; mouse model; neuron loss; novel; polyglutamine; protein complex; protein misfolding; repaired; targeted treatment

Huntington’s disease (HD) is a neurodegenerative disorder caused by an expansion of a CAG repeat tract within the huntingtin (HTT) gene, leading to neuronal death primarily in the striatum and the cortex. The CAG repeat is highly unstable and patients with longer inherited CAG repeats develop the disease at an earlier age. The repeat tract is also highly unstable in somatic cells. A high degree of age-dependent somatic expansion of the CAG repeat is observed in neurons of both the striatum and the cortex of HD patients, but not in unaffected brain regions like the cerebellum, indicating that somatic CAG repeat expansion is a driver of disease manifestation. Earlier disease onset is also associated with the length of uninterrupted CAG repeats and a concomitant increase in somatic instability. These findings further underscore the importance of somatic CAG expansion in disease manifestation. Recent genome-wide association studies in affected individuals have revealed the existence of genetic modifiers of the age of onset of the disease; these include several genes of the mismatch repair pathway (MMR) (MSH3, MLH1, PMS1, and PMS2) as well as FAN1, a DNA interstrand cross-link repair gene. Independently, studies in mouse models of HD have revealed that genetic knockout of the MMR genes, Msh2, Msh3, or Mlh1 reduces somatic instability of CAG repeats in the striatum. A role for MMR (the canonical function of which is to maintain genomic stability) in CAG repeat expansion is further supported by the observation that proteins in this pathway recognize and process extrahelical DNA extrusions formed by mishybridization of the two repeat-containing DNA strands. These findings support the view that aberrant MMR of such extrusions underlies the repeat expansion process. By contrast, knockout of Fan1 in an HD mouse model exacerbates CAG repeat expansion. We therefore hypothesize that two opposing DNA repair mechanisms act on CAG extrusions. Because MMR promotes repeat expansion, and FAN1 attenuates CAG expansion, the balance between these opposing pathways in affected neuronal cells likely determines the rate of repeat expansion and consequently, disease manifestation. Since the molecular details of either of these processes remains unclear, our overarching goal is to integrate biochemical, cellular, and phenotypic studies to develop a unified understanding of the mechanism of tissue/cell type specific CAG repeat expansion. In Aim 1, we will compare and contrast the molecular features and differing outcomes of the MutSβ- and FAN1- initiated CAG extrusion repair pathways. In Aim 2, we will determine the functional significance of protein complexes that associate with CAG extrusions. In Aim 3, we will define the role of PMS1 (as part of the MutLβ heterodimer) in regulation of CAG extrusion repair and repeat expansion. Completion of these studies will not only shed light on the mechanisms of CAG repeat expansion in HD, but also will inform our understanding of the emerging role of DNA repair in somatic instability that underlies other triplet repeat diseases like myotonic dystrophy type 1 and fragile-X related disorders.

亨廷顿氏病（HD）是一种神经退行性疾病，由体内CAG重复束扩张引起