Beyond CAG Repeats: The Multifaceted Role of Genetics in Huntington Disease

Genes, Journal Year: 2024, Volume and Issue: 15(6), P. 807 - 807

Published: June 19, 2024

Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by CAG expansion on the huntingtin (HTT) gene and characterized progressive motor, cognitive, neuropsychiatric decline. Recently, new genetic factors besides repeats have been implicated in pathogenesis. Most modifiers are involved DNA repair pathways and, as cause of loss CAA interruption HTT gene, they exert their main influence through somatic expansion. However, this mechanism might not be only driver HD pathogenesis, future studies warranted field. The aim present review to dissect many faces genetics from cis- trans-acting RNA toxicity, mitochondrial mutations, epigenetics factors. Exploring onset progression appears crucial elucidate but also improve prediction prevention, develop biomarkers response therapies, recognize therapeutic opportunities. Since same mechanisms described other repeat diseases, implications encompass whole spectrum these disorders.

Language: Английский

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Somatic CAG expansion in Huntington's disease is dependent on the MLH3 endonuclease domain, which can be excluded via splice redirection

Nucleic Acids Research, Journal Year: 2021, Volume and Issue: 49(7), P. 3907 - 3918

Published: Feb. 23, 2021

Somatic expansion of the CAG repeat tract that causes Huntington's disease (HD) is thought to contribute rate pathogenesis. Therefore, factors influencing are potential therapeutic targets. Genes in DNA mismatch repair pathway critical drivers somatic HD mouse models. Here, we have tested, using genetic and pharmacological approaches, role endonuclease domain protein MLH3 mice patient cells. A point mutation completely eliminated brain peripheral tissues a knock-in model (HttQ111). To test whether could be manipulated pharmacologically, delivered splice switching oligonucleotides redirect Mlh3 splicing exclude domain. Splice redirection an isoform lacking was associated with reduced expansion. Finally, patient-derived primary fibroblasts also significantly by redirecting endogenous domain-lacking isoform. These data indicate targeting slow HD, strategy may applicable across multiple disorders.

Language: Английский

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Huntington’s disease: nearly four decades of human molecular genetics

Human Molecular Genetics, Journal Year: 2021, Volume and Issue: 30(R2), P. R254 - R263

Published: June 21, 2021

Abstract Huntington’s disease (HD) is a devastating neurogenetic disorder whose familial nature and progressive course were first described in the 19th century but for which no disease-modifying treatment yet available. Through active participation of HD families, this has acted as flagship application human molecular genetic strategies to identify genes, understand pathogenesis rational targets development therapies.

Language: Английский

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Genetic topography and cortical cell loss in Huntington's disease link development and neurodegeneration

Brain, Journal Year: 2023, Volume and Issue: 146(11), P. 4532 - 4546

Published: Aug. 17, 2023

Abstract Cortical cell loss is a core feature of Huntington’s disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it unclear how genetic topography relates to cortical loss. Here, we explore biological processes and types underlying this relationship validate these using cell-specific post-mortem data. Eighty participants on average 15 from onset 71 controls were included. Using volumetric diffusion MRI extracted HD-specific whole brain maps where lower grey matter volume higher mean diffusivity, relative controls, used as proxies These combined with gene expression data Allen Human Brain Atlas (AHBA) investigate relating was positively correlated developmental genes (i.e. greater atrophy increased diffusivity) negatively synaptic metabolic that have been implicated in neurodegeneration. findings consistent for maps. As wild-type huntingtin known play role neurodevelopment, explored association between (HTT) across AHBA. Co-expression network analyses 134 human brains free neurodegenerative disorders also performed. HTT involved neurodevelopment while co-expression revealed associated processes. Expression weighted cell-type enrichment (EWCE) which specific HD associations validated single nucleus RNAseq (snRNAseq) brains. The transcriptomic profile preHD enriched astrocytes endothelial cells, neuronal microglial cells. Astrocyte-specific differentially expressed snRNAseq profile, microglial-specific profile. Our suggest may arise dual pathological processes, emerging consequence neurodevelopmental changes, at life, followed by neurodegeneration adulthood, targeting areas reduced genes. events result age-related death multiple types.

Language: Английский

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FAN1 removes triplet repeat extrusions via a PCNA- and RFC-dependent mechanism

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(33)

Published: Aug. 7, 2023

Human genome-wide association studies have identified FAN1 and several DNA mismatch repair (MMR) genes as modifiers of Huntington’s disease age onset. In animal models, prevents somatic expansion CAG triplet repeats, whereas MMR proteins promote this process. To understand the molecular basis these opposing effects, we evaluated nuclease function on extrahelical extrusions that represent key intermediates in repeat expansion. Here, describe a strand-directed, extrusion-provoked is activated by RFC, PCNA, ATP at physiological ionic strength. Activation manner results cleavage vicinity thereby leading to their removal human cell extracts. The role PCNA RFC confer strand directionality nuclease, reaction requires physical interaction between FAN1. Using extracts, show FAN1-dependent extrusion relies very short patch excision-repair mechanism competes with MutSβ-dependent which characterized longer excision tracts. These provide mechanistic for preventing could explain antagonistic effects onset/progression.

Language: Английский

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