FAN1 removes triplet repeat extrusions via a PCNA- and RFC-dependent mechanism DOI Creative Commons
Ashutosh S. Phadte, Mayuri Bhatia,

Hope Ebert

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(33)

Published: Aug. 7, 2023

Human genome-wide association studies have identified FAN1 and several DNA mismatch repair (MMR) genes as modifiers of Huntington’s disease age onset. In animal models, prevents somatic expansion CAG triplet repeats, whereas MMR proteins promote this process. To understand the molecular basis these opposing effects, we evaluated nuclease function on extrahelical extrusions that represent key intermediates in repeat expansion. Here, describe a strand-directed, extrusion-provoked is activated by RFC, PCNA, ATP at physiological ionic strength. Activation manner results cleavage vicinity thereby leading to their removal human cell extracts. The role PCNA RFC confer strand directionality nuclease, reaction requires physical interaction between FAN1. Using extracts, show FAN1-dependent extrusion relies very short patch excision-repair mechanism competes with MutSβ-dependent which characterized longer excision tracts. These provide mechanistic for preventing could explain antagonistic effects onset/progression.

Language: Английский

Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities DOI
Sarah J. Tabrizi, Carlos Estevez‐Fraga, Willeke M. C. van Roon‐Mom

et al.

The Lancet Neurology, Journal Year: 2022, Volume and Issue: 21(7), P. 645 - 658

Published: June 15, 2022

Language: Английский

Citations

205
Cell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum DOI Creative Commons
Kärt Mätlik,

Matthew Baffuto,

Laura Kus

et al.

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

Citations

58
From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington’s Disease Research DOI Open Access
Andrew Jiang, Renée R. Handley, Klaus Lehnert

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(16), P. 13021 - 13021

Published: Aug. 21, 2023

Huntington’s disease (HD) is a debilitating neurodegenerative genetic disorder caused by an expanded polyglutamine-coding (CAG) trinucleotide repeat in the huntingtin (HTT) gene. HD behaves as highly penetrant dominant likely acting through toxic gain of function mutant protein. Widespread cellular degeneration medium spiny neurons caudate nucleus and putamen are responsible for onset symptomology that encompasses motor, cognitive, behavioural abnormalities. Over past 150 years research since George Huntington published his description, plethora pathogenic mechanisms have been proposed with key themes including excitotoxicity, dopaminergic imbalance, mitochondrial dysfunction, metabolic defects, disruption proteostasis, transcriptional dysregulation, neuroinflammation. Despite identification characterisation causative gene mutation significant advances our understanding pathology recent years, disease-modifying intervention has not yet clinically approved. This review includes overview disease, from its aetiology to clinical presentation manifestation. An updated view molecular latest therapeutic developments will also be discussed.

Language: Английский

Citations

53
Neuropathogenesis-on-chips for neurodegenerative diseases DOI Creative Commons
Sarnai Amartumur, Huong Mai Nguyen, Thuy Huynh

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 12, 2024

Abstract Developing diagnostics and treatments for neurodegenerative diseases (NDs) is challenging due to multifactorial pathogenesis that progresses gradually. Advanced in vitro systems recapitulate patient-like pathophysiology are emerging as alternatives conventional animal-based models. In this review, we explore the interconnected pathogenic features of different types ND, discuss general strategy modelling NDs using a microfluidic chip, introduce organoid-on-a-chip next advanced relevant model. Lastly, overview how these models being applied academic industrial drug development. The integration chips, stem cells, biotechnological devices promises provide valuable insights biomedical research developing diagnostic therapeutic solutions NDs.

Language: Английский

Citations

26
Huntington’s Disease Pathogenesis: Two Sequential Components DOI Creative Commons
Eun Pyo Hong,

Marcy E. MacDonald,

Vanessa C. Wheeler

et al.

Journal of Huntington s Disease, Journal Year: 2021, Volume and Issue: 10(1), P. 35 - 51

Published: Feb. 9, 2021

Historically, Huntington’s disease (HD; OMIM #143100) has played an important role in the enormous advances human genetics seen over past four decades. This familial neurodegenerative disorder involves variable onset followed by consistent worsening of characteristic abnormal movements along with cognitive decline and psychiatric disturbances. HD was first autosomal for which genetic defect assigned to a position on chromosomes using only linkage analysis common DNA polymorphisms. discovery set off multitude similar studies other diseases, while gene, later renamed HTT, its vicinity chromosome 4p16.3 then acted as proving ground development technologies clone sequence genes based upon their genomic location, growing momentum such fueling Human Genome Project. The identification gene not yet led effective treatment, but continued genotype-phenotype relationships large subject populations, at HTT locus subsequently genome-wide, provided insights into pathogenesis that divide course two sequential, mechanistically distinct components.

Language: Английский

Citations

87
DNA Mismatch Repair and its Role in Huntington’s Disease DOI Creative Commons

Ravi R. Iyer,

Anna Pluciennik

Journal of Huntington s Disease, Journal Year: 2021, Volume and Issue: 10(1), P. 75 - 94

Published: Feb. 9, 2021

DNA mismatch repair (MMR) is a highly conserved genome stabilizing pathway that corrects replication errors, limits chromosomal rearrangements, and mediates the cellular response to many types of damage. Counterintuitively, MMR also involved in generation mutations, as evidenced by its role causing somatic triplet repeat expansion Huntington’s disease (HD) other neurodegenerative disorders. In this review, we discuss current state mechanistic knowledge review roles key enzymes pathway. We present evidence for mutagenic function CAG consider hypotheses have been proposed. Understanding may shed light on potential avenues therapeutic intervention HD.

Language: Английский

Citations

85
Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models DOI Creative Commons
Vanessa C. Wheeler, Vincent Dion

Journal of Huntington s Disease, Journal Year: 2021, Volume and Issue: 10(1), P. 123 - 148

Published: Feb. 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.

Language: Английский

Citations

74
Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis DOI Creative Commons

Ramita Dewan,

Ruth Chia, Jinhui Ding

et al.

Neuron, Journal Year: 2020, Volume and Issue: 109(3), P. 448 - 460.e4

Published: Nov. 26, 2020

Language: Английский

Citations

71
Propensity for somatic expansion increases over the course of life in Huntington disease DOI Creative Commons
Radhia Kacher, François‐Xavier Lejeune,

Sandrine Noël

et al.

eLife, Journal Year: 2021, Volume and Issue: 10

Published: May 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.

Language: Английский

Citations

62
Polyglutamine diseases DOI

Emma L. Bunting,

Joseph Hamilton, Sarah J. Tabrizi

et al.

Current Opinion in Neurobiology, Journal Year: 2021, Volume and Issue: 72, P. 39 - 47

Published: Sept. 3, 2021

Language: Английский

Citations

61