Cas9-mediated replacement of expanded CAG repeats in a pig model of Huntington’s disease

Nature Biomedical Engineering, Journal Year: 2023, Volume and Issue: 7(5), P. 629 - 646

Published: Feb. 16, 2023

Language: Английский

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Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: 25(7), P. 476 - 499

Published: March 11, 2024

Language: Английский

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Polyglutamine disorders: Pathogenesis and potential drug interventions

Life Sciences, Journal Year: 2024, Volume and Issue: 344, P. 122562 - 122562

Published: March 14, 2024

Language: Английский

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Genetic modifiers of repeat expansion disorders

Emerging Topics in Life Sciences, Journal Year: 2023, Volume and Issue: 7(3), P. 325 - 337

Published: Oct. 20, 2023

Repeat expansion disorders (REDs) are monogenic diseases caused by a sequence of repetitive DNA expanding above pathogenic threshold. A common feature the REDs is strong genotype-phenotype correlation in which major determinant age at onset (AAO) and disease progression length inherited repeat tract. Over disease-gene carrier's life, can expand somatic cells, through process hypothesised to drive progression. Despite being monogenic, individual phenotypically variable, exploring what genetic modifying factors this phenotypic variability has illuminated key mechanisms that group diseases. Disease phenotypes affected cognate gene found, location coding or non-coding regions presence interruptions. Human data, mouse models vitro have implicated disease-modifying effect repair pathways via mutation As such, developing an understanding these context expanded repeats could lead future therapies for REDs.

Language: Английский

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Ataxin‐2 sequesters Raptor into aggregates and impairs cellular mTORC1 signaling

FEBS Journal, Journal Year: 2024, Volume and Issue: 291(8), P. 1795 - 1812

Published: Feb. 3, 2024

Ataxin-2 (Atx2) is a polyglutamine (polyQ) protein, in which abnormal expansion of the polyQ tract can trigger protein aggregation and consequently cause spinocerebellar ataxia type 2 (SCA2), but mechanism underlying how Atx2 leads to proteinopathy remains elusive. Here, we investigate molecular cellular consequences by cell biology approaches. We have revealed that either normal or polyQ-expanded sequester Raptor, component mammalian target rapamycin complex 1 (mTORC1), into aggregates based on their specific interaction. Further research indicates N-terminal region (residues 1-784) are responsible for sequestration. Moreover, this sequestration suppression mTORC1 activity as represented down-regulation phosphorylated P70S6K, be reversed overexpression Raptor. As key regulator autophagy, also induces autophagy upregulating LC3-II reducing ULK1 levels. This study proposes sequesters Raptor aggregates, thereby impairing signaling inducing will beneficial better understanding pathogenesis SCA2 other diseases.

Language: Английский

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Solid-state nuclear magnetic resonance in the structural study of polyglutamine aggregation

Biochemical Society Transactions, Journal Year: 2024, Volume and Issue: 52(2), P. 719 - 731

Published: April 2, 2024

The aggregation of proteins into amyloid-like fibrils is seen in many neurodegenerative diseases. Recent years have much progress our understanding these misfolded protein inclusions, thanks to advances techniques such as solid-state nuclear magnetic resonance (ssNMR) spectroscopy and cryogenic electron microscopy (cryo-EM). However, multiple repeat-expansion-related disorders presented special challenges structural elucidation. This review discusses the role ssNMR analysis study aggregates associated with CAG repeat expansion disorders. In diseases, misfolding affect mutant expanded polyglutamine segments. most common disorder, Huntington's disease (HD), connected mutation huntingtin protein. Since discovery genetic causes for HD 1990s, steady has depended on integrative interdisciplinary use types techniques. heterogeneous dynamic features polyQ fibrils, particular those formed by N-terminal fragments, made challenging targets analysis. offered unique insights aspects aggregates. These include atomic-level structure core, but also measurements dynamics solvent accessibility non-core flanking domains fibrils' fuzzy coats. obtained shed new light pathogenic mechanisms behind this other

Language: Английский

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Review of Huntington’s Disease: From Basics to Advances in Diagnosis and Treatment

Journal of Neurology Research, Journal Year: 2022, Volume and Issue: 12(3), P. 93 - 113

Published: Oct. 1, 2022

We conducted the present review facing enormous growth of scientific knowledge in Huntington's disease (HD) and need for a practical update general neurologists. HD is devastating neurodegenerative autosomal dominant inheritance full penetrance, caused by an expansion cytosine-adenine-guanine (CAG) trinucleotide huntingtin gene located on chromosome 4. The clinical phenotype varies according to age presentation, but it mainly characterized cognitive, motor psychiatric disturbances. Many mechanisms were raised trying explain path neurodegeneration, including disruption proteostasis, transcription mitochondrial dysfunction as well direct toxicity. There has been tremendous progress regarding pathogenesis, management promising new therapeutic avenues disease-modifying treatments that pose challenge approach be taken movement disorders specialists J Neurol Res. 2022;12(3):93-113 doi: https://doi.org/10.14740/jnr721

Language: Английский

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Mechanisms underlying phenotypic variation in neurogenetic disorders

Nature Reviews Neurology, Journal Year: 2023, Volume and Issue: 19(6), P. 363 - 370

Published: May 18, 2023

Language: Английский

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Molecular and cellular characteristics of cerebrovascular cell types and their contribution to neurodegenerative diseases

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 29, 2025

Language: Английский

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Cerebellar lipid dysregulation in SCA3: A comparative study in patients and mice

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 106827 - 106827

Published: Feb. 1, 2025

Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited and belongs to family of nine diseases caused by a polyglutamine expansion in disease-causing protein. In SCA3, ATXN3 causes neuron loss disease-vulnerable brain regions, resulting progressive coordination ultimately death. There are no disease-modifying or preventative treatments for this uniformly fatal disorder. Recent studies demonstrate prominent white matter atrophy microstructural alterations regions SCA3 patients mouse models. However, major constituent - lipids remains understudied SCA3. study, we conducted first unbiased investigation focusing on cerebellum postmortem Liquid chromatography-mass spectrometry uncovered widespread lipid reductions with Lipid downregulation was recapitulated early- mid-stage models including transgenic YACQ84 Knock-in Q300 mice. End-stage mice displayed reduction content, highlighting targets that could benefit from early therapeutic intervention. contrast, Atxn3-Knock-out showed mild upregulation, emphasizing toxic gain-of-function mechanism underlying We conclude significantly altered establish platform continued exploration disease through interactive data visualization websites. Pronounced myelin-enriched suggest dysregulation underlie This study establishes basis future work elucidating mechanistic, biomarker, potential

Language: Английский

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