Cell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(3), P. 383 - 394

Published: Jan. 30, 2024

Abstract Brain region-specific degeneration and somatic expansions of the mutant Huntingtin ( mHTT ) CAG tract are key features Huntington’s disease (HD). However, relationships among expansions, death specific cell types molecular events associated with these processes not established. Here, we used fluorescence-activated nuclear sorting (FANS) deep profiling to gain insight into properties human striatum cerebellum in HD control donors. arise at striatal medium spiny neurons (MSNs), cholinergic interneurons cerebellar Purkinje neurons, ATXN3 MSNs from SCA3 higher levels MSH2 MSH3 (forming MutSβ), which can inhibit nucleolytic excision slip-outs by FAN1. Our data support a model necessary but may be sufficient for identify transcriptional changes toxicity.

Language: Английский

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Long somatic DNA-repeat expansion drives neurodegeneration in Huntington disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 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.

Language: Английский

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

Brain, Journal Year: 2024, Volume and Issue: 147(5), P. 1784 - 1798

Published: Feb. 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.

Language: Английский

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

Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Cell therapy for neurological disorders

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(10), P. 2756 - 2770

Published: Oct. 1, 2024

Language: Английский

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Accelerated epigenetic aging in Huntington’s disease involves polycomb repressive complex 1

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 11, 2025

Abstract Loss of epigenetic information during physiological aging compromises cellular identity, leading to de-repression developmental genes. Here, we assessed the epigenomic landscape vulnerable neurons in two reference mouse models Huntington neurodegenerative disease (HD), using cell-type-specific multi-omics, including temporal analysis at three stages via FANS-CUT&Tag. We show accelerated genes HD striatal neurons, involving histone re-acetylation and depletion H2AK119 ubiquitination H3K27 trimethylation marks, which are catalyzed by polycomb repressive complexes 1 2 (PRC1 PRC2), respectively. further identify a PRC1-dependent subcluster bivalent transcription factors that is re-activated neurons. This mechanism likely involves progressive paralog switching between PRC1-CBX genes, promotes upregulation normally low-expressed PRC1-CBX2/4/8 isoforms alongside down-regulation predominant these cells (e.g., CBX6/7). Collectively, our data provide evidence for

Language: Английский

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Standardizing the CAP Score in Huntington’s Disease by Predicting Age-at-Onset

Journal of Huntington s Disease, Journal Year: 2022, Volume and Issue: 11(2), P. 153 - 171

Published: April 19, 2022

Huntington's disease (HD) is an autosomal dominant, neurological caused by expanded CAG repeat near the N-terminus of huntingtin (HTT) gene. A leading theory concerning etiology HD that both onset and progression are driven cumulative exposure to effects mutant (or expanded) (mHTT). The CAG-Age-Product (CAP) score (i.e., product excess length age) a commonly used measure this exposure. CAP has been widely as predictor variety state variables in HD. utility somewhat diminished, however, lack agreement on its precise definition. most forms highly correlated so that, for purposes prediction, it makes little difference which used. However, reported values scores, based definitions, differ substantially magnitude when applied same data. This complicates process inter-study comparison.In paper, we propose standardized definition will resolve difficulty. Our standardization chosen = 100 at expected age diagnosis.Statistical methods include novel survival analysis methodology 13 landmarks taken from Enroll-HD database (PDS 5) comparisons with existing, gold standard, model.Useful by-products our work up-to-date, age-at-onset (AO) results refined AO model suitable use other contexts, discussion several useful properties have not previously noted literature introduction concept toxicity model.We suggest taking L 30 K 6.49 provides score, routine modeling clinical data

Language: Английский

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Cysteine metabolism and hydrogen sulfide signaling in Huntington’s disease

Free Radical Biology and Medicine, Journal Year: 2022, Volume and Issue: 186, P. 93 - 98

Published: May 10, 2022

Language: Английский

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Cell Type Specific CAG Repeat Expansions and Toxicity of Mutant Huntingtin in Human Striatum and Cerebellum

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 24, 2023

Brain region-specific degeneration and somatic expansions of the mutant Huntingtin (mHTT) CAG tract are key features Huntington's disease (HD). However, relationships between expansions, death specific cell types, molecular events associated with these processes not established. Here we employed fluorescence-activated nuclear sorting (FANS) deep profiling to gain insight into properties types human striatum cerebellum in HD control donors. arise striatal medium spiny neurons (MSNs) cholinergic interneurons, cerebellar Purkinje neurons, at

Language: Английский

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Therapeutic targeting of mismatch repair proteins in triplet repeat expansion diseases

DNA repair, Journal Year: 2025, Volume and Issue: 147, P. 103817 - 103817

Published: Feb. 15, 2025

Language: Английский

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