Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities

The Lancet Neurology, Год журнала: 2022, Номер 21(7), С. 645 - 658

Опубликована: Июнь 15, 2022

Язык: Английский

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Long somatic DNA-repeat expansion drives neurodegeneration in Huntington disease

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 20, 2024

Abstract Huntington Disease (HD) is a fatal genetic disease in which most striatal projection neurons (SPNs) degenerate. The central biological question about HD pathogenesis has been how the disease-causing DNA repeat expansion (CAG n ) huntingtin ( HTT gene leads to neurodegeneration after decades of apparent latency. Inherited alleles with longer CAG hasten onset; length this also changes over time, generating somatic mosaicism, and genes that regulate DNA-repeat stability can influence age-at-onset. To understand relationship between cell’s CAG-repeat its state, we developed single-cell method for measuring together genome-wide RNA expression. We found expands from 40-45 CAGs 100-500+ HD-vulnerable SPNs but not other cell types, these long expansions acquired at different times by individual SPNs. Surprisingly, 40 150 had no effect upon expression – 150-500+ shared profound gene-expression changes. These involved hundreds genes, escalated alongside further expansion, eroded positive then negative features neuronal identity, culminated senescence/apoptosis genes. Rates neuron loss across stages reflected rates entered biologically distorted state. Our results suggest repeats undergo quiet then, as they asynchronously cross high threshold, cause degenerate quickly asynchronously. conclude that, any moment course HD, have an innocuous (but unstable) gene, process almost all neuron’s life.

Язык: Английский

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A CAG repeat threshold for therapeutics targeting somatic instability in Huntington's disease

Brain, Год журнала: 2024, Номер 147(5), С. 1784 - 1798

Опубликована: Фев. 22, 2024

The Huntington's disease mutation is a CAG repeat expansion in the huntingtin gene that results an expanded polyglutamine tract protein. unstable and expansions of hundreds CAGs have been detected post-mortem brains. age onset can be predicted partially from length as measured blood. Onset also determined by genetic modifiers, which six cases involve variation DNA mismatch repair pathways genes. Knocking-out specific genes mouse models prevents somatic expansion. Taken together, these led to hypothesis brains required for pathogenesis. Therefore, pathogenic threshold brain longer than (CAG)40, blood, currently unknown. MSH3 has become major focus therapeutic development, unlike other genes, nullizygosity does not cause malignancies associated with deficiency. Potential treatments targeting under development include therapy, biologics small molecules, will assessed efficacy disease. zQ175 knock-in model carries approximately (CAG)185 develops early molecular pathological phenotypes extensively characterized. we crossed mutant allele onto heterozygous homozygous Msh3 knockout backgrounds determine maximum benefit this model. Ablation prevented throughout periphery, reduction 50% decreased rate This had no effect on deposition aggregation nuclei striatal neurons, nor dysregulated transcriptional profile. contrasts ablating shorter expansions. further neurons accelerate neuropathological phenotypes. It striking highly repeats similar size humans before 2 years age, indicating Given trajectory carriers unknown, our study underlines importance administering instability possible.

Язык: Английский

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Long somatic DNA-repeat expansion drives neurodegeneration in Huntington’s disease

Cell, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models

Journal of Huntington s Disease, Год журнала: 2021, Номер 10(1), С. 123 - 148

Опубликована: Фев. 9, 2021

At fifteen different genomic locations, the expansion of a CAG/CTG repeat causes neurodegenerative or neuromuscular disease, most common being Huntington’s disease and myotonic dystrophy type 1. These disorders are characterized by germline somatic instability causative mutations. Repeat lengthening, expansion, in leads to an earlier age onset more severe symptoms next generation. In cells, is thought precipitate rate disease. The mechanisms underlying not well understood. Here we review mammalian model systems that have been used study instability, modifiers identified these systems. Mouse models demonstrated prominent roles for proteins mismatch repair pathway as critical drivers which also suggested recent genome-wide association studies humans. We draw attention network connections between across several might indicate crosstalk context could provide hypotheses further validation discovery. Overall, data dynamics be modulated altering levels DNA metabolic proteins, their regulation, interaction with chromatin, direct perturbation tract. Applying novel methodologies technologies this exciting area research will needed gain deeper mechanistic insight can harnessed therapies aimed at preventing promoting contraction.

Язык: Английский

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Propensity for somatic expansion increases over the course of life in Huntington disease

eLife, Год журнала: 2021, Номер 10

Опубликована: Май 13, 2021

Recent work on Huntington disease (HD) suggests that somatic instability of CAG repeat tracts, which can expand into the hundreds in neurons, explains clinical outcomes better than length inherited allele. Here, we measured expansion blood samples collected from same 50 HD mutation carriers over a twenty-year period, along with post-mortem tissue 15 adults and 7 fetal carriers, to examine expansions at different stages life. Post-mortem brains, as previously reported, had greatest expansions, but cortex virtually none. Somatic increased age, despite cells being short-lived compared was driven mostly by length, then age sampling interaction between these two variables. Expansion rates were higher symptomatic subjects. These data lend support proposed computational model instability-driven disease.

Язык: Английский

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Polyglutamine diseases

Current Opinion in Neurobiology, Год журнала: 2021, Номер 72, С. 39 - 47

Опубликована: Сен. 3, 2021

Язык: Английский

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

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Апрель 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.

Язык: Английский

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Therapeutic validation of MMR-associated genetic modifiers in a human ex vivo model of Huntington disease

The American Journal of Human Genetics, Год журнала: 2024, Номер 111(6), С. 1165 - 1183

Опубликована: Май 14, 2024

The pathological huntingtin (HTT) trinucleotide repeat underlying Huntington disease (HD) continues to expand throughout life. Repeat length correlates both with earlier age at onset (AaO) and faster progression, making slowing its expansion an attractive therapeutic approach. Genome-wide association studies have identified candidate variants associated altered AaO many found in DNA mismatch repair (MMR)-associated genes. We examine whether lowering expression of these genes affects the rate human ex vivo models using HD iPSCs iPSC-derived striatal medium spiny neuron-enriched cultures. generated a stable CRISPR interference iPSC line which we can specifically efficiently lower gene from donor carrying over 125 CAG repeats. Lowering each member MMR complexes MutS (MSH2, MSH3, MSH6), MutL (MLH1, PMS1, PMS2, MLH3), LIG1 resulted characteristic deficiencies. Reduced MSH2, MLH1 slowed largest degree, while either or MLH3 it lesser degree. These effects were recapitulated cultures where factor was lowered. CRISPRi-mediated key levels feasibly achievable by current approaches able effectively slow HTT tract. highlight members family as potential targets pathogenic aim delay progression potentially other disorders exhibiting somatic instability.

Язык: Английский

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CAG repeat mosaicism is gene specific in spinocerebellar ataxias

The American Journal of Human Genetics, Год журнала: 2024, Номер 111(5), С. 913 - 926

Опубликована: Апрель 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.

Язык: Английский

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