Huntington’s disease iPSC models—using human patient cells to understand the pathology caused by expanded CAG repeats DOI Open Access
Julia Kaye,

Terry Reisine,

Steven Finkbeiner

и другие.

Faculty Reviews, Год журнала: 2022, Номер 11

Опубликована: Июнь 28, 2022

A major advance in the study of Huntington’s disease (HD) has been development human models employing induced pluripotent stem cells (iPSCs) derived from patients with HD. Because iPSCs provide an unlimited source and can be obtained large numbers HD patients, they are a uniquely valuable tool for investigating mechanisms discovering potential disease-modifying therapeutics. Here, we summarize some important findings pathophysiology that have emerged studies patient-derived iPSC lines. retain genome actual mutations patient, cell to investigate genetic contributions disease. advantages over other models. While iPSC-based technology erases epigenetic marks, newly developed transdifferentiation methods now let us factors control expression mutant huntingtin (mHTT). Human lines allow how endogenous levels mHTT affect health, contrast often rely on overexpressing protein. differentiated into neurons disease-related such as astrocytes different brain regions regional differences process, well cell-cell dependencies involved HD-associated neurodegeneration. They also serve tissue impact CAG repeat instability, which is neurodegeneration brain. powerful model system identify modifiers may onset, progression, symptomatology, providing novel molecular targets drug discovery.

Язык: Английский

Aberrant splicing in Huntington’s disease accompanies disrupted TDP-43 activity and altered m6A RNA modification DOI Creative Commons
Thai B. Nguyen, Ricardo Miramontes,

Carlos Chillón-Marinas

и другие.

Nature Neuroscience, Год журнала: 2025, Номер unknown

Опубликована: Янв. 6, 2025

Язык: Английский

Процитировано

2
Therapeutic validation of MMR-associated genetic modifiers in a human ex vivo model of Huntington disease DOI Creative Commons
Ross Ferguson,

Robert Goold,

Lucy A. Coupland

и другие.

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

Процитировано

10
Somatic CAG repeat instability in intermediate alleles of the HTT gene and its potential association with a clinical phenotype DOI Creative Commons
Ainara Ruiz de Sabando, Marc Ciosi, Arkaitz Galbete

и другие.

European Journal of Human Genetics, Год журнала: 2024, Номер 32(7), С. 770 - 778

Опубликована: Март 4, 2024

Abstract Huntington disease (HD) is a neurodegenerative disorder caused by ≥36 CAGs in the HTT gene. Intermediate alleles (IAs) (27–35 CAGs) are not considered HD-causing, but their potential association with neurocognitive symptoms remains controversial. As somatic CAG expansion influences HD onset, we hypothesised that IAs somatically unstable, and may drive phenotypic presentation some IA carriers. We quantified expansions MiSeq sequencing blood DNA of 164 subjects 191 (symptomatic control) carriers, brain symptomatic 33 carrier. also performed genotype-phenotype analysis. The phenotype carriers was characterised motor (85%), cognitive (27%) and/or behavioural (29%) signs, late (58.7 ± 18.6 years), CAG-dependent, age at onset. displayed were age-dependent DNA, 0.4% 0.01% molecules expanding year, respectively. Somatic +1 +2 detected individual CAGs, highest frequency putamen (10.3%) lowest cerebellum (4.8%). different vs. control In conclusion, show found no HD-like phenotypes. It plausible, however, IAs, close to pathological threshold predisposing genetic background, could manifest symptoms.

Язык: Английский

Процитировано

8
CAG repeat mosaicism is gene specific in spinocerebellar ataxias DOI Creative Commons
Radhia Kacher, François‐Xavier Lejeune,

I. Rodenhiser David

и другие.

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

Процитировано

8
Msh3 and Pms1 Set Neuronal CAG-repeat Migration Rate to Drive Selective Striatal and Cortical Pathogenesis in HD Mice DOI
Nan Wang,

Shasha Zhang,

Peter Langfelder

и другие.

Опубликована: Июль 13, 2024

SUMMARY Modifiers of Huntington’s disease (HD) include mismatch repair (MMR) genes; however, their underlying disease-altering mechanisms remain unresolved. Knockout (KO) alleles for 9 HD GWAS modifiers/MMR genes were crossed to the Q140 Huntingtin (mHtt) knock-in mice probe such mechanisms. Four KO strongly ( Msh3 and Pms1 ) or moderately Msh2 Mlh1 rescue a triad adult-onset, striatal medium-spiny-neuron (MSN)-selective phenotypes: somatic Htt DNA CAG-repeat expansion, transcriptionopathy, mHtt protein aggregation. Comparatively, cortex also exhibits an analogous, but later-onset, pathogenic that is -dependent. Remarkably, Q140/homozygous Msh3-KO lacks visible aggregates in brain, even at advanced ages (20-months). Moreover, -deficiency prevents synaptic marker loss, astrogliosis, locomotor impairment mice. Purified MSN nuclei exhibit highly linear age-dependent repeat expansion (i.e. migration), with modal-CAG increasing +8.8 repeats/month (R 2 =0.98). This rate reduced 2.3 0.3 heterozygous homozygous alleles, respectively. Our study defines thresholds below which there are no detectable nuclear neuropil aggregates. Mild transcriptionopathy can still occur stabilized 140-CAG repeats, majority transcriptomic changes due expansion. analysis reveals 479 expression levels correlated length MSNs. Thus, our mechanistically connects selective neuronal vulnerability HD, set migration drive repeat-length dependent pathogenesis; provides preclinical platform targeting these suppression across brain regions. One Sentence Summary genetic drivers sequential cortical pathogenesis by mediating vulnerable neurons.

Язык: Английский

Процитировано

8
Recent Advances in the Genetics of Ataxias: An Update on Novel Autosomal Dominant Repeat Expansions DOI Creative Commons
David Pellerin, Pablo Iruzubieta,

Isaac Xu

и другие.

Current Neurology and Neuroscience Reports, Год журнала: 2025, Номер 25(1)

Опубликована: Янв. 16, 2025

Язык: Английский

Процитировано

1
Mutation and selection processes regulating short tandem repeats give rise to genetic and phenotypic diversity across species DOI Creative Commons
Max A. Verbiest, Mikhail O. Maksimov, Jin Ye

и другие.

Journal of Evolutionary Biology, Год журнала: 2022, Номер 36(2), С. 321 - 336

Опубликована: Окт. 26, 2022

Short tandem repeats (STRs) are units of 1-6 bp that repeat in a fashion DNA. Along with single nucleotide polymorphisms and large structural variations, they among the major genomic variants underlying genetic, likely phenotypic, divergence. STRs experience mutation rates orders magnitude higher than other well-studied genotypic variants. Frequent copy number changes result wide range alleles, provide unique opportunities for modulating complex phenotypes through variation length. While classical studies have identified key roles individual STR loci, advent improved sequencing technology, high-quality genome assemblies diverse species, bioinformatics methods genome-wide analysis now enable more systematic study across evolutionary ranges. In this review, we explore selection processes affect evolution, how these give rise to varying patterns both within species. Finally, review recent examples functional adaptive linked STRs.

Язык: Английский

Процитировано

36
Current and emerging treatment modalities for spinocerebellar ataxias DOI

Shaila Ghanekar,

Sheng‐Han Kuo,

Joseph S. Staffetti

и другие.

Expert Review of Neurotherapeutics, Год журнала: 2022, Номер 22(2), С. 101 - 114

Опубликована: Янв. 26, 2022

Spinocerebellar ataxias (SCA) are a group of rare neurodegenerative diseases that dramatically affect the lives affected individuals and their families. Despite having clear understanding SCA's etiology, there no current symptomatic or neuroprotective treatments approved by FDA.Research efforts have greatly expanded possibilities for potential treatments, including both pharmacological non-pharmacological interventions. Great attention is also being given to novel therapeutics based in gene therapy, neurostimulation, molecular targeting. This review article will address advances treatment SCA what interventions on horizon.SCA highly complex multifaceted disease family with majority research emphasizing pharmacologic therapies. As pre-clinical trials clinical other conditions illuminate efficacy modifying therapies such as AAV-mediated therapy ASOs, addressing at pre-symptomatic stage increasingly promising.

Язык: Английский

Процитировано

31
A Glimpse of Molecular Biomarkers in Huntington’s Disease DOI Open Access
Silvia Martí Martínez, Luis M. Valor

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(10), С. 5411 - 5411

Опубликована: Май 12, 2022

Huntington’s disease (HD) is a devastating neurodegenerative disorder that caused by an abnormal expansion of CAG repeats in the Huntingtin (HTT) gene. Although main symptomatology explained alterations at level central nervous system, predominantly affecting basal ganglia, peripheral component being increasingly acknowledged. Therefore, manifestation complex and variable among carriers, introducing uncertainty appearance specific signs, age onset severity disease. The monogenic nature allows precise diagnosis, but use biomarkers with prognostic value still needed to achieve clinical management patients individual manner. In addition, we need tools evaluate patient’s response potential therapeutic approaches. this review, provide succinct summary most interesting molecular have been assessed patients, mostly obtained from body fluids such as cerebrospinal fluid, blood saliva.

Язык: Английский

Процитировано

29
Antagonistic roles of canonical and Alternative-RPA in disease-associated tandem CAG repeat instability DOI Creative Commons

Terence Gall-Duncan,

Jennifer Luo,

Carla-Marie Jurkovic

и другие.

Cell, Год журнала: 2023, Номер 186(22), С. 4898 - 4919.e25

Опубликована: Окт. 1, 2023

Язык: Английский

Процитировано

17