Huntington’s disease affects mitochondrial network dynamics predisposing to pathogenic mitochondrial DNA mutations

Brain, Journal Year: 2024, Volume and Issue: 147(6), P. 2009 - 2022

Published: Jan. 9, 2024

Huntington's disease (HD) predominantly affects the brain, causing a mixed movement disorder, cognitive decline and behavioural abnormalities. It also causes peripheral phenotype involving skeletal muscle. Mitochondrial dysfunction has been reported in tissues of HD models, including muscle, lymphoblast fibroblast cultures from patients with HD. Mutant huntingtin protein (mutHTT) expression can impair mitochondrial quality control accelerate ageing. Here, we obtained fresh human post-mitotic tissue expressing mutated HTT allele at physiological levels since birth, primary cell lines CAG repeat expansion mutation carriers matched healthy volunteers to examine whether such exists Using ultra-deep DNA (mtDNA) sequencing, showed an accumulation mtDNA mutations affecting oxidative phosphorylation. Tissue proteomics indicated impairments maintenance increased biogenesis less efficient phosphorylation (lower complex I IV activity). In full-length mutHTT lines, fission-inducing stress resulted normal mitophagy. contrast, high N-terminal fragments promoted fission slower, dynamic Expression due somatic nuclear instability thus affect network dynamics mitophagy, leading pathogenic mutations. We show that life-long mutant indicative Thus, genomic may not be limited DNA, where it results length particularly vulnerable cells as striatal neurons. addition efforts targeting causative mutation, promoting health complementary strategy treating diseases

Language: Английский

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Splice modulators target PMS1 to reduce somatic expansion of the Huntington’s disease-associated CAG repeat

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 12, 2024

Abstract Huntington’s disease (HD) is a dominant neurological disorder caused by an expanded HTT exon 1 CAG repeat that lengthens huntingtin’s polyglutamine tract. Lowering mutant huntingtin has been proposed for treating HD, but genetic modifiers implicate somatic expansion as the driver of onset. We find branaplam and risdiplam, small molecule splice modulators lower promoting pseudoexon inclusion, also decrease unstable in engineered cell model. Targeted CRISPR-Cas9 editing shows this effect not due to lowering, pointing instead inclusion PMS1 . Homozygous heterozygous inactivation reduces expansion, supporting modifier HD potential target therapeutic intervention. Although modulation provides one strategy, genome-wide transcriptomics emphasize consideration cell-type specific effects polymorphic variation at both off-target sites.

Language: Английский

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CAG repeat mosaicism is gene specific in spinocerebellar ataxias

The American Journal of Human Genetics, Journal Year: 2024, Volume and Issue: 111(5), P. 913 - 926

Published: April 15, 2024

Expanded CAG repeats in coding regions of different genes are the most common cause dominantly inherited spinocerebellar ataxias (SCAs). These unstable through germline, and larger lead to earlier onset. We measured somatic expansion blood samples collected from 30 SCA1, 50 SCA2, 74 SCA3, SCA7 individuals over a mean interval 8.5 years, along with postmortem tissues fetal examine at stages life. showed that mosaicism increases time. Expansion levels significantly among SCAs correlate repeat lengths. The level is greater who manifest disease compared those do not yet display symptoms. Brain SCA have expansions blood. cerebellum has lowest studied brain regions, high expression ATXNs DNA repair genes. This was opposite cortices, highest lower Fetal cortices did show instability. study shows increasingly during life individuals, gene- tissue-specific patterns.

Language: Английский

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In vivo CRISPR–Cas9 genome editing in mice identifies genetic modifiers of somatic CAG repeat instability in Huntington’s disease

Nature Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Huntington's disease, one of more than 50 inherited repeat expansion disorders1, is a dominantly neurodegenerative disease caused by CAG in HTT2. Inherited length the primary determinant age onset, with human genetic studies underscoring that driven length-dependent propensity to further expand brain3–9. Routes slowing somatic expansion, therefore, hold promise for disease-modifying therapies. Several DNA repair genes, notably mismatch pathway, modify mouse models10. To identify novel modifiers we used CRISPR–Cas9 editing knock-in mice enable vivo screening expansion-modifier candidates at scale. This included testing onset modifier genes emerging from genome-wide association as well interactions between providing insight into pathways underlying and potential therapeutic targets. A strategy identifies new contribute disease.

Language: Английский

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Antisense oligonucleotide–mediated MSH3 suppression reduces somatic CAG repeat expansion in Huntington’s disease iPSC–derived striatal neurons

Science Translational Medicine, Journal Year: 2025, Volume and Issue: 17(785)

Published: Feb. 12, 2025

Expanded CAG alleles in the huntingtin ( HTT ) gene that cause neurodegenerative disorder Huntington’s disease (HD) are genetically unstable and continue to expand somatically throughout life, driving HD onset progression. MSH3, a DNA mismatch repair protein, modifies progression by this somatic repeat expansion process. MSH3 is relatively tolerant of loss-of-function variation humans, making it potential therapeutic target. Here, we show an -targeting antisense oligonucleotide (ASO) effectively engaged with its RNA target induced pluripotent stem cell (iPSC)–derived striatal neurons obtained from patient carrying 125 repeats (the iPSC line). ASO treatment led dose-dependent reduction subsequent stalling these neurons. Bulk sequencing revealed safe profile for reduction, even when reduced >95%. Maximal knockdown also slowed otherwise accelerated rate, derived line where FAN1 was knocked out CRISPR-Cas9 editing. Last, created knock-in mouse model expressing human demonstrated effective vivo after treatment. Our study shows ASO-mediated can prevent iPSC–derived neurons, highlighting approach.

Language: Английский

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Interrupting sequence variants and age of onset in Huntington's disease: clinical implications and emerging therapies

The Lancet Neurology, Journal Year: 2020, Volume and Issue: 19(11), P. 930 - 939

Published: Oct. 21, 2020

Language: Английский

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The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

Journal of Huntington s Disease, Journal Year: 2021, Volume and Issue: 10(1), P. 7 - 33

Published: Feb. 9, 2021

The discovery in the early 1990s of expansion unstable simple sequence repeats as causative mutation for a number inherited human disorders, including Huntington’s disease (HD), opened up new era genetics and provided explanations some old problems. In particular, an inverse association between age at onset, unprecedented levels germline instability, biased toward further expansion, explanation wide symptomatic variability anticipation observed HD many these disorders. were also revealed to be somatically process that is expansion-biased, age-dependent tissue-specific, features are now increasingly recognised contributory age-dependence, progressive nature tissue specificity symptoms HD, least related With much data deriving from affected individuals, model systems, somatic expansions have been arise cell division-independent manner critical target tissues via mechanism involving key components DNA mismatch repair pathway. These insights approaches thinking about how could treated by suppressing novel protein targets intervention. Exciting times lie ahead turning into therapies

Language: Английский

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What is the Pathogenic CAG Expansion Length in Huntington’s Disease?

Journal of Huntington s Disease, Journal Year: 2021, Volume and Issue: 10(1), P. 175 - 202

Published: Feb. 9, 2021

Huntington's disease (HD) (OMIM 143100) is caused by an expanded CAG repeat tract in the HTT gene. The inherited length known to expand further somatic and germline cells HD subjects. Age at onset of inversely correlated with length, but modulated a series genetic modifiers which are most likely act on that permit it expand. Longer repeats more prone expansions, this expansion age dependent tissue-specific. Given expands through life subjects develop mid-life, implies degenerate, be longer than length. These findings suggest two thresholds- permits expansion, intracellular pathogenic threshold, above become dysfunctional die. This two-step mechanism has been previously proposed modelled mathematically give threshold 115 (95% confidence intervals 70- 165 CAG). Empirically, difficult determine. Clues from studies people models HD, other diseases tracts, place between 60- 100 CAG, towards upper part range. We assess evidence discuss how manifest might better determined. Knowing cellular would informative for both understanding deploying treatments.

Language: Английский

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Spinocerebellar ataxia clinical trials: opportunities and challenges

Annals of Clinical and Translational Neurology, Journal Year: 2021, Volume and Issue: 8(7), P. 1543 - 1556

Published: May 21, 2021

Abstract The spinocerebellar ataxias (SCAs) are a group of dominantly inherited diseases that share the defining feature progressive cerebellar ataxia. disease process, however, is not confined to cerebellum; other areas brain, in particular, brainstem, also affected, resulting high burden morbidity and mortality. Currently, there no disease‐modifying treatments for SCAs, but preclinical research has led development therapeutic agents ripe testing patients. Unfortunately, due rarity these their slow variable progression, substantial hurdles overcome conducting clinical trials. While epidemiological features SCAs immutable, feasibility trials being addressed through combination strategies. These include improvements outcome measures, identification imaging fluid biomarkers, innovations trial design. In this review, we highlight current challenges initiating discuss pathways researchers clinicians mitigate harness opportunities development.

Language: Английский

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Antagonistic roles of canonical and Alternative-RPA in disease-associated tandem CAG repeat instability

Cell, Journal Year: 2023, Volume and Issue: 186(22), P. 4898 - 4919.e25

Published: Oct. 1, 2023

Language: Английский

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