FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington’s disease DOI Creative Commons

Robert Goold,

Joseph Hamilton, Thomas Menneteau

и другие.

Cell Reports, Год журнала: 2021, Номер 36(9), С. 109649 - 109649

Опубликована: Авг. 1, 2021

CAG repeat expansion in the HTT gene drives Huntington's disease (HD) pathogenesis and is modulated by DNA damage repair pathways. In this context, interaction between FAN1, a DNA-structure-specific nuclease, MLH1, member of mismatch pathway (MMR), not defined. Here, we identify highly conserved SPYF motif at N terminus FAN1 that binds to MLH1. Our data support model where has two distinct functions stabilize repeats. On one hand, it MLH1 restrict its recruitment MSH3, thus inhibiting assembly functional MMR complex would otherwise promote expansion. other promotes accurate via nuclease activity. These highlight potential avenue for HD therapeutics attenuating somatic

Язык: Английский

Mendelian inheritance revisited: dominance and recessiveness in medical genetics DOI
Johannes Zschocke, Peter H. Byers, Andrew O.M. Wilkie

и другие.

Nature Reviews Genetics, Год журнала: 2023, Номер 24(7), С. 442 - 463

Опубликована: Фев. 20, 2023

Язык: Английский

Процитировано

52
Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases DOI Creative Commons
Dillon J. Rinauro, Fabrizio Chiti, Michele Vendruscolo

и другие.

Molecular Neurodegeneration, Год журнала: 2024, Номер 19(1)

Опубликована: Фев. 20, 2024

The conversion of native peptides and proteins into amyloid aggregates is a hallmark over 50 human disorders, including Alzheimer's Parkinson's diseases. Increasing evidence implicates misfolded protein oligomers produced during the formation process as primary cytotoxic agents in many these devastating conditions. In this review, we analyze processes by which are formed, their structures, physicochemical properties, population dynamics, mechanisms cytotoxicity. We then focus on drug discovery strategies that target ability to disrupt cell physiology trigger degenerative processes.

Язык: Английский

Процитировано

41
Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases DOI Creative Commons
Yao Xiang, Xiaohua Song,

Dingxin Long

и другие.

Archives of Toxicology, Год журнала: 2024, Номер 98(3), С. 579 - 615

Опубликована: Янв. 24, 2024

Abstract This article provides an overview of the background knowledge ferroptosis in nervous system, as well key role nuclear factor E2-related 2 (Nrf2) regulating ferroptosis. The takes Alzheimer's disease (AD), Parkinson's (PD), Huntington's (HD), and amyotrophic lateral sclerosis (ALS) starting point to explore close association between Nrf2 ferroptosis, which is clear significant importance for understanding mechanism neurodegenerative diseases (NDs) based on oxidative stress (OS). Accumulating evidence links pathogenesis NDs. As progresses, damage antioxidant excessive OS, altered expression levels, especially inhibition by lipid peroxidation inhibitors adaptive enhancement signaling, demonstrate potential clinical significance detecting identifying targeted therapy neuronal loss mitochondrial dysfunction. These findings provide new insights possibilities treatment prevention

Язык: Английский

Процитировано

25
Stem cell therapies for neurological disorders: current progress, challenges, and future perspectives DOI Creative Commons
Ramyar Rahimi Darehbagh,

Seyedeh Asrin Seyedoshohadaei,

Rojin Ramezani

и другие.

European journal of medical research, Год журнала: 2024, Номер 29(1)

Опубликована: Июль 25, 2024

Stem cell-based therapies have emerged as a promising approach for treating various neurological disorders by harnessing the regenerative potential of stem cells to restore damaged neural tissue and circuitry. This comprehensive review provides an in-depth analysis current state cell applications in primary conditions, including Parkinson's disease (PD), Alzheimer's (AD), amyotrophic lateral sclerosis (ALS), multiple (MS), stroke, spinal cord injury (SCI), other related disorders. The begins with detailed introduction biology, discussing types, sources, mechanisms action therapies. It then critically examines preclinical evidence from animal models early human trials investigating safety, feasibility, efficacy different such embryonic (ESCs), mesenchymal (MSCs), (NSCs), induced pluripotent (iPSCs). While ESCs been studied extensively models, clinical primarily focused on adult MSCs NSCs, well iPSCs their derivatives. We assess research each type, highlighting limitations conditions. synthesizes key findings recent, high-quality studies condition, manufacturing, delivery methods, therapeutic outcomes. replace lost neurons directly reconstruct circuits is highlighted, emphasizes critical role paracrine immunomodulatory mediating effects most article also explores challenges associated translating into practice, issues sourcing, scalability, regulatory considerations. Furthermore, it discusses future directions opportunities advancing treatments, gene editing, biomaterials, personalized iPSC-derived therapies, novel strategies. concludes emphasizing transformative revolutionizing treatment while acknowledging need rigorous trials, standardized protocols, multidisciplinary collaboration realize full promise.

Язык: Английский

Процитировано

20
Associations Between Diabetes Mellitus and Neurodegenerative Diseases DOI Open Access

Leszek Szablewski

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(2), С. 542 - 542

Опубликована: Янв. 10, 2025

Diabetes mellitus (DM) and neurodegenerative diseases/disturbances are worldwide health problems. The most common chronic conditions diagnosed in persons 60 years older type 2 diabetes (T2DM) cognitive impairment. It was found that is a major risk for decline, dementia, Parkinson's disease (PD), Alzheimer's (AD), Huntington's (HD), amyotrophic lateral sclerosis (ALS) other disorders. Different mechanisms of associations between these diseases have been suggested. For example, it postulated an impaired intracellular insulin signaling pathway, together with hyperglycemia hyperinsulinemia, may cause pathological changes, such as dysfunction the mitochondria, oxidative stress inflammatory responses, etc. association diseases, well associations, needs further investigation. aim this review to describe mellitus, especially 1 (T1DM) selected i.e., disease, sclerosis. Suggested also described.

Язык: Английский

Процитировано

2
O-GlcNAcylation in health and neurodegenerative diseases DOI Creative Commons

Byeong Eun Lee,

Pann‐Ghill Suh, Jae‐Ick Kim

и другие.

Experimental & Molecular Medicine, Год журнала: 2021, Номер 53(11), С. 1674 - 1682

Опубликована: Ноя. 1, 2021

Abstract O-GlcNAcylation is a posttranslational modification that adds O-linked β- N -acetylglucosamine (O-GlcNAc) to serine or threonine residues of many proteins. This protein interacts with key cellular pathways involved in transcription, translation, and proteostasis. Although ubiquitous throughout the body, O-GlcNAc particularly abundant brain, various proteins commonly found at synapses are O-GlcNAcylated. Recent studies have demonstrated modulation brain alters synaptic neuronal functions. Furthermore, altered associated either etiology pathology numerous neurodegenerative diseases, while manipulation exerts neuroprotective effects against these diseases. detailed molecular mechanisms underlying functional roles remain unclear, critical for regulating diverse neural functions, its levels change during normal pathological aging. In this review, we will highlight importance

Язык: Английский

Процитировано

89
DNA Mismatch Repair and its Role in Huntington’s Disease DOI Creative Commons

Ravi R. Iyer,

Anna Pluciennik

Journal of Huntington s Disease, Год журнала: 2021, Номер 10(1), С. 75 - 94

Опубликована: Фев. 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.

Язык: Английский

Процитировано

85
Human Sirtuin Regulators: The “Success” Stories DOI Creative Commons
Alyson M. Curry,

Dawanna S. White,

Dickson Donu

и другие.

Frontiers in Physiology, Год журнала: 2021, Номер 12

Опубликована: Окт. 21, 2021

The human sirtuins are a group of NAD + -dependent protein deacylases. They “erase” acyl modifications from lysine residues in various cellular targets including histones, transcription factors, and metabolic enzymes. Through these far-reaching activities, regulate diverse array biological processes ranging gene to energy metabolism. Human have been intensely pursued by both academia industry as therapeutic for broad spectrum diseases such cancer, neurodegenerative diseases, disorders. last two decades witnessed flood small molecule sirtuin regulators. However, there remain relatively few compounds targeting clinical development. This reflects the inherent issues concerning development isoform-selective potent molecules with good drug-like properties. In this article, regulators that advanced into trials will be discussed details “successful” examples future drug Special attention is given discovery compounds, mechanism action, pharmacokinetics analysis, formulation, well outcomes observed trials.

Язык: Английский

Процитировано

71
An RNA-targeting CRISPR–Cas13d system alleviates disease-related phenotypes in Huntington’s disease models DOI Creative Commons
Kathryn H. Morelli, Qian Wu, Maya L. Gosztyla

и другие.

Nature Neuroscience, Год журнала: 2022, Номер 26(1), С. 27 - 38

Опубликована: Дек. 12, 2022

Abstract Huntington’s disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by CAG trinucleotide expansion in exon 1 of the huntingtin ( HTT ) gene. Since reduction pathogenic mutant messenger RNA therapeutic, we developed allele-sensitive EX RNA-targeting CRISPR–Cas13d system (Cas13d–CAG that eliminates toxic fibroblasts derived from patients with HD and induced pluripotent stem cell-derived neurons. We show intrastriatal delivery Cas13d–CAG via an adeno-associated viral vector selectively reduces mRNA protein levels striatum heterozygous zQ175 mice, model HD. This also led to improved motor coordination, attenuated striatal atrophy aggregates. These phenotypic improvements lasted for at least eight months without adverse effects minimal off-target transcriptomic effects. Taken together, demonstrate proof principle as therapeutic approach HD, strategy implications treatment other disorders.

Язык: Английский

Процитировано

67
Propensity for somatic expansion increases over the course of life in Huntington disease DOI Creative Commons
Radhia Kacher, François‐Xavier Lejeune,

Sandrine Noël

и другие.

eLife, Год журнала: 2021, Номер 10

Опубликована: Май 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.

Язык: Английский

Процитировано

62