Decoding TDP-43: the molecular chameleon of neurodegenerative diseases DOI Creative Commons

Jixiang Zeng,

Can Luo, Yang Jiang

et al.

Acta Neuropathologica Communications, Journal Year: 2024, Volume and Issue: 12(1)

Published: Dec. 31, 2024

TAR DNA-binding protein 43 (TDP-43) has emerged as a critical player in neurodegenerative disorders, with its dysfunction implicated wide spectrum of diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer's disease (AD). This comprehensive review explores the multifaceted roles TDP-43 both physiological pathological contexts. We delve into TDP-43's crucial functions RNA metabolism, splicing regulation, mRNA stability, miRNA biogenesis. Particular emphasis is placed on recent discoveries regarding involvement DNA interactions chromatin dynamics, highlighting broader impact gene expression genome stability. The also examines complex pathogenesis TDP-43-related discussing protein's propensity for aggregation, effects mitochondrial function, non-cell autonomous impacts glial cells. provide an in-depth analysis pathology across various conditions, from well-established associations ALS FTLD to emerging such Huntington's Niemann-Pick C disease. potential therapeutic target explored, focus developments targeting cryptic exon inclusion other TDP-43-mediated processes. synthesizes current knowledge biology pathology, offering insights central role neurodegeneration promising avenues future research interventions.

Language: Английский

The roles of intrinsically disordered proteins in neurodegeneration DOI Creative Commons
Kagistia Hana Utami, Satoru Morimoto, Yasue Mitsukura

et al.

Biochimica et Biophysica Acta (BBA) - General Subjects, Journal Year: 2025, Volume and Issue: unknown, P. 130772 - 130772

Published: Feb. 1, 2025

Language: Английский

Citations

1
Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances DOI Creative Commons
Mei Dang, Longjiang Wu, Xiaoying Zhang

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 141677 - 141677

Published: March 1, 2025

Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a critical RNA/DNA-binding involved in various cellular processes, including RNA splicing, transcription regulation, and stability. Mislocalization aggregation of TDP-43 the cytoplasm are key features pathogenesis several neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD). This review provides comprehensive retrospective prospective analysis research, highlighting structural insights, significant milestones, evolving understanding its physiological pathological functions. We delineate five major stages from initial discovery as hallmark neurodegeneration to recent advances liquid-liquid phase separation (LLPS) behavior interactions with processes. Furthermore, we assess therapeutic strategies targeting pathology, categorizing approaches into direct indirect interventions, alongside modulating aberrant LLPS. propose that future research will focus on three areas: polymorphisms for disease-specific therapeutics, exploring dual temporal-spatial modulation TDP-43, advancing nano-therapy. More importantly, emphasize importance TDP-43's functional repertoire at mesoscale, which bridges molecular functions broader offers foundational framework development.

Language: Английский

Citations

1
Adenosine Triphosphate: The Primordial Molecule That Controls Protein Homeostasis and Shapes the Genome–Proteome Interface DOI Creative Commons
Jianxing Song

Biomolecules, Journal Year: 2024, Volume and Issue: 14(4), P. 500 - 500

Published: April 19, 2024

Adenosine triphosphate (ATP) acts as the universal energy currency that drives various biological processes, while nucleic acids function to store and transmit genetic information for all living organisms. Liquid-liquid phase separation (LLPS) represents common principle formation of membrane-less organelles (MLOs) composed proteins rich in intrinsically disordered regions (IDRs) acids. Currently, IDRs are well recognized facilitate LLPS through dynamic multivalent interactions, precise mechanisms by which ATP affect still remain elusive. This review summarizes recent NMR results on human FUS, TDP-43, viral nucleocapsid (N) protein SARS-CoV-2, modulated acids, revealing following: (1) binds folded domains overlapping with nucleic-acid-binding interfaces; (2) interplay biphasically modulate competitively binding pockets Arg/Lys within IDRs; (3) energy-independently induces folding highest efficiency known so far. As likely emerged prebiotic monomeric world, a pivotal mechanism concentrate compartmentalize rare molecules forming primordial cells, appears control homeostasis shape genome-proteome interfaces throughout evolutionary trajectory, from origins modern cells.

Language: Английский

Citations

5
Mutations in human prion-like domains: pathogenic but not always amyloidogenic DOI Creative Commons
Andrea Bartolomé-Nafría, Javier García‐Pardo, Salvador Ventura

et al.

Prion, Journal Year: 2024, Volume and Issue: 18(1), P. 28 - 39

Published: March 21, 2024

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are multifunctional proteins with integral roles in RNA metabolism and the regulation of alternative splicing. These typically contain prion-like domains low complexity (PrLDs or LCDs) that govern their assembly into either functional pathological amyloid fibrils. To date, over 60 mutations targeting LCDs hnRNPs have been identified associated a spectrum neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD). The cryo-EM structures fibrils formed by different recently elucidated, those hnRNPA1, hnRNPA2, hnRNPDL-2, TDP-43, FUS. In this review, we discuss structural features these assemblies, placing particular emphasis on scrutinizing impact prevalent disease-associated mapping within LCDs. By performing systematic energy calculations, reveal prevailing trend destabilizing effects induced structure, challenging traditionally assumed correlation between pathogenicity amyloidogenic propensity. Understanding molecular basis discrepancy might provide insights for developing targeted therapeutic strategies to combat hnRNP-associated diseases.

Language: Английский

Citations

4
Introducing the Role of Genotoxicity in Neurodegenerative Diseases and Neuropsychiatric Disorders DOI Open Access
Glen E. Kisby,

David M. Wilson,

Peter S. Spencer

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 7221 - 7221

Published: June 29, 2024

Decades of research have identified genetic and environmental factors involved in age-related neurodegenerative diseases and, to a lesser extent, neuropsychiatric disorders. Genomic instability, i.e., the loss genome integrity, is common feature among both (mayo-trophic lateral sclerosis, Parkinson's disease, Alzheimer's disease) psychiatric (schizophrenia, autism, bipolar depression) instability associated with accumulation persistent DNA damage activation response (DDR) pathways, as well pathologic neuronal cell or senescence. Typically, DDR signaling ensures that genomic proteomic homeostasis are maintained dividing cells, including neural progenitors, post-mitotic neurons. However, dysregulation these protective responses, part due aging insults, contributes progressive development and/or In this Special Issue, we introduce highlight overlap between disorders, emerging clinical, genomic, molecular evidence for contributions aberrant repair. Our goal illuminate importance subject uncover possible treatment prevention strategies relevant devastating brain diseases.

Language: Английский

Citations

4
Biomolecular condensates and disease pathogenesis DOI
Ke Ruan, Ge Bai, Yanshan Fang

et al.

Science China Life Sciences, Journal Year: 2024, Volume and Issue: 67(9), P. 1792 - 1832

Published: July 17, 2024

Language: Английский

Citations

4
Emerging regulatory mechanisms and functions of biomolecular condensates: implications for therapeutic targets DOI Creative Commons
Soyoung Jeon, Yong‐Duck Chung, Jae‐Sung Lim

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 6, 2025

Cells orchestrate their processes through complex interactions, precisely organizing biomolecules in space and time. Recent discoveries have highlighted the crucial role of biomolecular condensates-membrane-less assemblies formed condensation proteins, nucleic acids, other molecules-in driving efficient dynamic cellular processes. These condensates are integral to various physiological functions, such as gene expression intracellular signal transduction, enabling rapid finely tuned responses. Their ability regulate signaling pathways is particularly significant, it requires a careful balance between flexibility precision. Disruption this can lead pathological conditions, including neurodegenerative diseases, cancer, viral infections. Consequently, emerged promising therapeutic targets, with potential offer novel approaches disease treatment. In review, we present recent insights into regulatory mechanisms by which influence pathways, roles health disease, strategies for modulating condensate dynamics approach. Understanding these emerging principles may provide valuable directions developing effective treatments targeting aberrant behavior diseases.

Language: Английский

Citations

0
Connecting the Dots: Stress Granule and Cardiovascular Diseases DOI Creative Commons

Gaowei Yang,

Yiming Wang, Jianchun Guo

et al.

Journal of Cardiovascular Translational Research, Journal Year: 2025, Volume and Issue: unknown

Published: April 14, 2025

Language: Английский

Citations

0
Supercharging design of an anti-lysozyme Fab antibody to regulate ligand-dependent reversible aggregation DOI Creative Commons
Keisuke Kasahara, Makoto Nakakido, Daisuke Kuroda

et al.

Polymer Journal, Journal Year: 2025, Volume and Issue: unknown

Published: April 25, 2025

Language: Английский

Citations

0
Phase separation in DNA repair: orchestrating the cellular response to genomic stability DOI Creative Commons
Jinghao Deng, Zhiping Du, Lei Li

et al.

PeerJ, Journal Year: 2025, Volume and Issue: 13, P. e19402 - e19402

Published: May 2, 2025

DNA repair is a hierarchically organized, spatially and temporally regulated process involving numerous factors that respond to various types of damage. Despite decades research, the mechanisms by which these are recruited depart from sites have been subject intrigue. Recent advancements in field increasingly highlighted role phase separation as critical facilitator efficiency repair. This review emphasizes how enhances concentration coordination at damage sites, optimizing efficiency. Understanding dysregulation can impair alter nuclear organization, potentially leading diseases such cancer neurodegenerative disorders, crucial. manuscript provides comprehensive understanding pivotal repair, sheds light on current suggests potential future directions for research therapeutic interventions.

Language: Английский

Citations

0