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

et al.

Cell Reports, Journal Year: 2021, Volume and Issue: 36(9), P. 109649 - 109649

Published: Aug. 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

Language: Английский

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

Kunhong Zhong

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: April 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.

Language: Английский

Citations

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

Stefania Sarno

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: May 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.

Language: Английский

Citations

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

et al.

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

Published: June 15, 2022

Language: Английский

Citations

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

Mackenzie Wendy Ferguson,

Connor J. Kennedy,

Thulani H. Palpagama

et al.

Journal of Central Nervous System Disease, Journal Year: 2022, Volume and Issue: 14

Published: April 1, 2022

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

Language: Английский

Citations

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

Nature reviews. Neuroscience, Journal Year: 2023, Volume and Issue: 24(8), P. 457 - 473

Published: June 19, 2023

Language: Английский

Citations

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

et al.

Science Advances, Journal Year: 2022, Volume and Issue: 8(3)

Published: Jan. 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.

Language: Английский

Citations

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

et al.

Cells, Journal Year: 2022, Volume and Issue: 11(9), P. 1520 - 1520

Published: May 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.

Language: Английский

Citations

74
Mitochondrial dysfunction in neurodegenerative disorders DOI Creative Commons

Madelyn Klemmensen,

Seth H. Borrowman,

Colin Pearce

et al.

Neurotherapeutics, Journal Year: 2023, Volume and Issue: 21(1), P. e00292 - e00292

Published: Dec. 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.

Language: Английский

Citations

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

et al.

Trends in Neurosciences, Journal Year: 2023, Volume and Issue: 46(3), P. 176 - 198

Published: Jan. 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.

Language: Английский

Citations

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

et al.

Molecular Biomedicine, Journal Year: 2023, Volume and Issue: 4(1)

Published: Oct. 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.

Language: Английский

Citations

58