Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington’s disease decades before clinical motor diagnosis

Nature Medicine, Год журнала: 2025, Номер unknown

Опубликована: Янв. 17, 2025

Язык: 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, Год журнала: 2025, Номер unknown

Опубликована: Янв. 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.

Язык: 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, Год журнала: 2025, Номер 17(785)

Опубликована: Фев. 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.

Язык: Английский

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Defining genes and pathways that modify huntingtin CAG repeat somatic instability in vivo

Nature Genetics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

Язык: Английский

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PMS2 has both pro-mutagenic and anti-mutagenic effects on repeat instability in the Repeat Expansion Diseases

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

Опубликована: Авг. 13, 2024

Abstract Genome Wide Association studies (GWAS) have implicated PMS2 as a modifier of somatic expansion in Huntington’s disease (HD), one >45 known Repeat Expansion Diseases (REDs). is subunit the MutLα complex, major component mismatch repair (MMR) system, pathway that involved generation expansions many different REDs. However, while MLH3, second MutL MutLγ, required for all expansions, has been shown to protect against some model systems but drive others. To better understand PMS2’s behavior, we compared effect loss tissues an HD mouse (CAG/CTG repeats) and Fragile X-related disorders (FXDs), result from CGG/CCG repeat expansion. Mice heterozygous Pms2 show increased most expansion-prone both models. null mice repeats decreased Thus, previously reported differences effects do not reflect fundamentally roles played by REDs, rather paradoxical cellular contexts. These findings important implications only mechanism development therapeutic approaches reduce pathology generated expansion, also our understanding normal MMR.

Язык: Английский

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When repetita no-longer iuvant: somatic instability of the CAG triplet in Huntington’s disease

Nucleic Acids Research, Год журнала: 2024, Номер unknown

Опубликована: Дек. 14, 2024

Abstract Trinucleotide repeats in DNA exhibit a dual nature due to their inherent instability. While rapid expansion can diversify gene expression during evolution, exceeding certain threshold lead diseases such as Huntington’s disease (HD), neurodegenerative condition, triggered by >36 C–A–G exon 1 of the Huntingtin gene. Notably, discovery somatic instability (SI) tract allows these mutations, inherited from an affected parent, further expand throughout patient’s lifetime, resulting mosaic brain with specific neurons exhibiting variable and often extreme CAG lengths, ultimately leading death. Genome-wide association studies have identified genetic variants—both cis trans, including mismatch repair modifiers—that modulate SI, shown blood cells, influence HD’s age onset. This review will explore evidence for SI HD its role pathogenesis, well therapeutic implications findings. We conclude emphasizing urgent need reliable methods quantify diagnostic prognostic purposes.

Язык: Английский

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Intersection of the Fragile X-related disorders and the DNA damage response

DNA repair, Год журнала: 2024, Номер 144, С. 103785 - 103785

Опубликована: Ноя. 7, 2024

Язык: Английский

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Structural and Dynamical Properties of Nucleic Acid Hairpins Implicated in Trinucleotide Repeat Expansion Diseases

Biomolecules, Год журнала: 2024, Номер 14(10), С. 1278 - 1278

Опубликована: Окт. 10, 2024

Dynamic mutations in some human genes containing trinucleotide repeats are associated with severe neurodegenerative and neuromuscular disorders-known as Trinucleotide (or Triplet) Repeat Expansion Diseases (TREDs)-which arise when the repeat number of triplets expands beyond a critical threshold. While mechanisms causing DNA triplet expansion complex remain largely unknown, it is now recognized that expandable lead to formation nucleotide configurations atypical structural characteristics play crucial role TREDs. These nonstandard nucleic acid forms include single-stranded hairpins, Z-DNA, triplex structures, G-quartets slipped-stranded duplexes. Of these, hairpin structures most prolific largest TREDs have therefore been focus recent single-molecule FRET experiments molecular dynamics investigations. Here, we review dynamical properties hairpins emerged from these studies implications for mechanisms. The will be on CAG, GAC, CTG GTC their stems, atomistic stability, important played by interrupts.

Язык: Английский

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Navigating triplet repeats sequencing: concepts, methodological challenges and perspective for Huntington’s disease

Nucleic Acids Research, Год журнала: 2024, Номер unknown

Опубликована: Дек. 2, 2024

The accurate characterization of triplet repeats, especially the overrepresented CAG is increasingly relevant for several reasons. First, germline expansion repeats above a gene-specific threshold causes multiple neurodegenerative disorders; instance, Huntington's disease (HD) triggered by >36 in huntingtin (HTT) gene. Second, extreme expansions up to 800 have been found specific cell types affected disease. Third, synonymous single nucleotide variants within repeat stretch influence age onset. Thus, new sequencing-based protocols that profile both length and exact sequence are crucial. Various strategies enrich target gene over background, along with sequencing platforms bioinformatic pipelines, under development. This review discusses concepts, challenges, methodological opportunities analyzing using HD as case study. Starting traditional approaches, we will explore how methods evolved meet increasing scientific demands. We also highlight experimental aiming provide guide diagnostic therapeutic purposes.

Язык: Английский

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Genomic characterization of Huntington’s disease genetic modifiers informs drug target tractability

Brain Communications, Год журнала: 2024, Номер 7(1)

Опубликована: Дек. 24, 2024

Huntington's disease is caused by a CAG repeat in the

Язык: Английский

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