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

Targeted protein degradation: mechanisms, strategies and application DOI Creative Commons
Lin Zhao, Jia Zhao,

Kunhong Zhong

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Апрель 4, 2022

Abstract Traditional drug discovery mainly focuses on direct regulation of protein activity. The development and application activity modulators, particularly inhibitors, has been the mainstream in development. In recent years, PROteolysis TArgeting Chimeras (PROTAC) technology emerged as one most promising approaches to remove specific disease-associated proteins by exploiting cells’ own destruction machinery. addition PROTAC, many different targeted degradation (TPD) strategies including, but not limited to, molecular glue, Lysosome-Targeting Chimaera (LYTAC), Antibody-based PROTAC (AbTAC), are emerging. These technologies have only greatly expanded scope TPD, also provided fresh insights into discovery. Here, we summarize advances major TPD technologies, discuss their potential applications, hope provide a prime for both biologists chemists who interested this vibrant field.

Язык: Английский

Процитировано

405
Protein kinase CK2: a potential therapeutic target for diverse human diseases DOI Creative Commons
Christian Borgo, Claudio D’Amore,

Stefania Sarno

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2021, Номер 6(1)

Опубликована: Май 17, 2021

Abstract CK2 is a constitutively active Ser/Thr protein kinase, which phosphorylates hundreds of substrates, controls several signaling pathways, and implicated in plethora human diseases. Its best documented role cancer, where it regulates practically all malignant hallmarks. Other well-known functions are infections; particular, viruses exploit host cell for their life cycle. Very recently, also SARS-CoV-2, the virus responsible COVID-19 pandemic, has been found to enhance activity induce phosphorylation substrates (either viral proteins). considered an emerging target neurological diseases, inflammation autoimmune disorders, diverse ophthalmic pathologies, diabetes, obesity. In addition, associated with cardiovascular as cardiac ischemia–reperfusion injury, atherosclerosis, hypertrophy. The hypothesis considering inhibition cystic fibrosis therapies entertained many years. Moreover, psychiatric disorders syndromes due mutations have recently identified. On these bases, increasingly attractive various fields medicine, advantage that very specific effective inhibitors already available. Here, we review literature on implication different pathologies evaluate its potential pharmacological light most recent findings.

Язык: Английский

Процитировано

242
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

и другие.

The Lancet Neurology, Год журнала: 2022, Номер 21(7), С. 645 - 658

Опубликована: Июнь 15, 2022

Язык: Английский

Процитировано

203
Current and Possible Future Therapeutic Options for Huntington’s Disease DOI Creative Commons

Mackenzie Wendy Ferguson,

Connor J. Kennedy,

Thulani H. Palpagama

и другие.

Journal of Central Nervous System Disease, Год журнала: 2022, Номер 14

Опубликована: Апрель 1, 2022

Huntington's disease (HD) is an autosomal neurodegenerative that characterized by excessive number of CAG trinucleotide repeats within the huntingtin gene (

Язык: Английский

Процитировано

80
Alternative splicing in neurodegenerative disease and the promise of RNA therapies DOI
David Nikom, Sika Zheng

Nature reviews. Neuroscience, Год журнала: 2023, Номер 24(8), С. 457 - 473

Опубликована: Июнь 19, 2023

Язык: Английский

Процитировано

77
Targeted gene silencing in the nervous system with CRISPR-Cas13 DOI Creative Commons
Jackson E. Powell, Colin K.W. Lim, Ramya Krishnan

и другие.

Science Advances, Год журнала: 2022, Номер 8(3)

Опубликована: Янв. 19, 2022

Cas13 nucleases are a class of programmable RNA-targeting CRISPR effector proteins that capable silencing target gene expression in mammalian cells. Here, we demonstrate RfxCas13d, ortholog with favorable characteristics to other family members, can be delivered the mouse spinal cord and brain silence neurodegeneration-associated genes. Intrathecally delivering an adeno-associated virus vector encoding RfxCas13d variant programmed superoxide dismutase 1 (SOD1), protein whose mutation cause amyotrophic lateral sclerosis, reduced SOD1 mRNA by >50% improved outcomes model disorder. We further show intrastriatally huntingtin (HTT), is causative for Huntington’s disease, led ~50% reduction HTT brain. Our results establish as versatile platform knocking down nervous system.

Язык: Английский

Процитировано

75
RhoA Signaling in Neurodegenerative Diseases DOI Creative Commons
Sissel Ida Schmidt, Morten Blaabjerg, Kristine Freude

и другие.

Cells, Год журнала: 2022, Номер 11(9), С. 1520 - 1520

Опубликована: Май 1, 2022

Ras homolog gene family member A (RhoA) is a small GTPase of the Rho involved in regulating multiple signal transduction pathways that influence diverse range cellular functions. RhoA and many its downstream effector proteins are highly expressed nervous system, implying an important role for signaling neurons glial cells. Indeed, emerging evidence points toward aberrant neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s Huntington’s amyotrophic lateral sclerosis. In this review, we summarize current knowledge regulation functions with emphasis on therapeutic potential inhibition neurodegeneration.

Язык: Английский

Процитировано

74
Mitochondrial dysfunction in neurodegenerative disorders DOI Creative Commons

Madelyn Klemmensen,

Seth H. Borrowman,

Colin Pearce

и другие.

Neurotherapeutics, Год журнала: 2023, Номер 21(1), С. e00292 - e00292

Опубликована: Дек. 19, 2023

Recent advances in understanding the role of mitochondrial dysfunction neurodegenerative diseases have expanded opportunities for neurotherapeutics targeting mitochondria to alleviate symptoms and slow disease progression. In this review, we offer a historical account biology disease. Additionally, summarize current knowledge normal physiology pathogenesis dysfunction, disease, therapeutics recent therapeutic advances, as well future directions function. A focus is placed on reactive oxygen species their disruption telomeres effects epigenome. The etiology progression Alzheimer's amyotrophic lateral sclerosis, Parkinson's Huntington's are discussed depth. Current clinical trials mitochondria-targeting discussed.

Язык: Английский

Процитировано

69
The foundation and architecture of precision medicine in neurology and psychiatry DOI Creative Commons
Harald Hampel, Peng Gao, Jeffrey L. Cummings

и другие.

Trends in Neurosciences, Год журнала: 2023, Номер 46(3), С. 176 - 198

Опубликована: Янв. 13, 2023

Neurological and psychiatric diseases have high degrees of genetic pathophysiological heterogeneity, irrespective clinical manifestations. Traditional medical paradigms focused on late-stage syndromic aspects these diseases, with little consideration the underlying biology. Advances in disease modeling methodological design paved way for development precision medicine (PM), an established concept oncology growing attention from other specialties. We propose a PM architecture central nervous system built four converging pillars: multimodal biomarkers, systems medicine, digital health technologies, data science. discuss Alzheimer's (AD), area significant unmet need, as case-in-point proposed framework. AD can be seen one most advanced PM-oriented models compelling catalyzer towards neuroscience drug healthcare practice.

Язык: Английский

Процитировано

67
The mechanism of ferroptosis and its related diseases DOI Creative Commons
Shijian Feng, Dan Tang, Yichang Wang

и другие.

Molecular Biomedicine, Год журнала: 2023, Номер 4(1)

Опубликована: Окт. 16, 2023

Abstract Ferroptosis, a regulated form of cellular death characterized by the iron-mediated accumulation lipid peroxides, provides novel avenue for delving into intersection metabolism, oxidative stress, and disease pathology. We have witnessed mounting fascination with ferroptosis, attributed to its pivotal roles across diverse physiological pathological conditions including developmental processes, metabolic dynamics, oncogenic pathways, neurodegenerative cascades, traumatic tissue injuries. By unraveling intricate underpinnings molecular machinery, contributors, signaling conduits, regulatory networks governing researchers aim bridge gap between intricacies this unique mode multifaceted implications health disease. In light rapidly advancing landscape ferroptosis research, we present comprehensive review aiming at extensive in origins progress human diseases. This concludes careful analysis potential treatment approaches carefully designed either inhibit or promote ferroptosis. Additionally, succinctly summarized therapeutic targets compounds that hold promise targeting within various facet underscores burgeoning possibilities manipulating as strategy. summary, enriched insights both investigators practitioners, while fostering an elevated comprehension latent translational utilities. revealing basic processes investigating possibilities, crucial resource scientists medical aiding deep understanding effects situations.

Язык: Английский

Процитировано

58