Progress in the role and mechanism of TDP-43 DOI
Rongbing Li

New discovery., Journal Year: 2024, Volume and Issue: unknown, P. 1 - 8

Published: Sept. 20, 2024

Background: TAR DNA-binding protein 43 kDa (TDP-43) has been shown to play an important role in the development of neurodegenerative diseases, but mechanism is still under study. Methods: By utilizing “TDP43”, “disease”, and “mechanism” as keywords, 200 related studies were retrieved downloaded from Pubmed database, including 60 articles. We summarized progress understanding TDP-43 over past two years, focusing on disease systems classification upstream downstream, connection, improvement, formation. Results: TDP-43, when abnormally aggregated, phosphorylated, or mislocalized, plays a key pathological diseases. Additionally, its impact normal reproductive cell formation, development, quantity, activity, well insulin secretion activation intestinal epithelial necrosis, should not be overlooked. Mechanistically, we identified relationship between expression factors, Enterovirus D68 (EV-D68), Heterogeneous Nuclear Ribonucleoprotein D (HNRNPD AUF1), Endoplasmic Reticulum Protein 57 (ERp57), Progranulin (PGRN), downstream factors such Meiotic Recombination Spo11 (Spo11), AMP-Activated Kinase (AMPK), Double-Strand-Break Repair Rad21 Homolog (Rad21L), IκB (IKK), TDP-43. Conclusion: neurodegeneration, which, phosphorylation, EV-d68, HNRNPD.

Language: Английский

Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence DOI Creative Commons
Joy Mitra, Manohar Kodavati, Prakash Dharmalingam

et al.

Acta Neuropathologica Communications, Journal Year: 2025, Volume and Issue: 13(1)

Published: March 8, 2025

Abstract TDP-43 mislocalization and aggregation are key pathological features of amyotrophic lateral sclerosis (ALS)- frontotemporal dementia (FTD). However, existing transgenic hTDP-43 WT or ∆NLS-overexpression animal models primarily focus on late-stage proteinopathy. To complement these to study the early-stage motor neuron-specific pathology during pre-symptomatic phases disease progression, we generated a new endogenous knock-in (KI) mouse model using combination CRISPR/Cas9 FLEX Cre-switch strategy for conditional expression mislocalized Tdp-43∆NLS variant Tdp-43. This is expressed either in whole body (WB) specifically neurons (MNs) two distinct models. These mice exhibit loss nuclear Tdp-43, with concomitant cytosolic accumulation targeted cells, leading increased DNA double-strand breaks (DSBs), signs inflammation, associated cellular senescence. Notably, unlike which functionally interacts Xrcc4 Ligase 4, DSB repair proteins non-homologous end-joining (NHEJ) pathway, mutant sequesters them into aggregates, exacerbating neuronal damage brain. The also myogenic degeneration hindlimb soleus muscles deficits, consistent characteristics neuron (MND). Our findings reveal progressive degenerative mechanisms expressing mutant, independent Tdp-43 overexpression other confounding factors. Thus, this unique KI model, displays molecular phenotypic proteinopathy, offers significant opportunity characterize progression MND further opens avenues developing repair-targeted approaches treating pathology-linked neurodegenerative diseases.

Language: Английский

Citations

1
Technical Assessment of Motor and Behavioral Tests in Rodent Models of Multiple Sclerosis DOI Creative Commons
Ola Mohamed-Fathy Kamal, Doddy Denise Ojeda-Hernández, B. Selma-Calvo

et al.

Journal of Integrative Neuroscience, Journal Year: 2025, Volume and Issue: 24(2)

Published: Feb. 21, 2025

Background: Multiple sclerosis (MS) is a neurodegenerative disorder characterized by progressive motor and cognitive impairments, affecting millions worldwide. It significantly reduces patients’ quality of life imposes burden on health systems. Despite advances in understanding MS, there no cure, highlighting the need for effective therapeutic strategies. Preclinical animal models are critical gaining insights into MS pathophysiology treatments. However, these fail to fully replicate complexity human making it essential choose appropriate behavioral tests evaluate their efficacy. Purpose: This review examines various used preclinical models, discussing strengths limitations. The goal guide researchers selecting most while providing how performed analyzed. Methods: We reviewed detailing test procedures evaluating advantages disadvantages. Results: offers comprehensive overview that aids choosing suitable studies, improving accuracy reliability research. Conclusions: Understanding limitations crucial informed decisions, leading better experimental designs and, ultimately, more interventions MS.

Language: Английский

Citations

0
TDP-43 dysregulation impairs cholesterol metabolism linked with myelination defects DOI Creative Commons
Irene García-Toledo, Juan M. Godoy-Corchuelo, Luis C. Fernández-Beltrán

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Abstract TDP-43 is a nuclear protein encoded by the TARDBP gene, which forms pathological aggregates in various neurodegenerative diseases, collectively known as proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These diseases are characterized multiple mechanisms, with disruptions lipid regulatory pathways emerging critical factor. However, role of regulation brain homeostasis potential connection dysfunction to myelin alterations proteionopathies remain poorly understood, despite fact that lipids, particularly cholesterol, comprise nearly 70% myelin. To investigate causal relationship between cholesterol homeostasis, we conducted multi-omics analyses (lipidomics, transcriptomics, functional splicing) on frontal cortex from TardbpM323K/M323K knock-in mouse model. Lipidomic analysis revealed related membrane composition droplet accumulation, affecting cholesterol-related species. We found higher droplets accumulation primary fibroblast derived these mice, well mutant mice. Similarly, immunohistochemical detection marker was post-mortem cortex, gray white matter, FTLD-TDP patients compared non-neurological controls. Transcriptomic showed pathology led transcriptional dysregulation genes essential for production maintenance. identified impaired metabolism, mainly through downregulation endogenous synthesis, alongside upregulated transport pathways, further replicated transcriptomic datasets. Collectively, our findings suggest disrupts potentially compromising integrity.

Language: Английский

Citations

0
Challenges of modelling TDP-43 pathology in mice DOI Creative Commons
José Miguel Brito Armas,

Lucas Taoro-González,

Elizabeth Fisher

et al.

Mammalian Genome, Journal Year: 2025, Volume and Issue: unknown

Published: April 29, 2025

Language: Английский

Citations

0
Progress in the role and mechanism of TDP-43 DOI
Rongbing Li

New discovery., Journal Year: 2024, Volume and Issue: unknown, P. 1 - 8

Published: Sept. 20, 2024

Background: TAR DNA-binding protein 43 kDa (TDP-43) has been shown to play an important role in the development of neurodegenerative diseases, but mechanism is still under study. Methods: By utilizing “TDP43”, “disease”, and “mechanism” as keywords, 200 related studies were retrieved downloaded from Pubmed database, including 60 articles. We summarized progress understanding TDP-43 over past two years, focusing on disease systems classification upstream downstream, connection, improvement, formation. Results: TDP-43, when abnormally aggregated, phosphorylated, or mislocalized, plays a key pathological diseases. Additionally, its impact normal reproductive cell formation, development, quantity, activity, well insulin secretion activation intestinal epithelial necrosis, should not be overlooked. Mechanistically, we identified relationship between expression factors, Enterovirus D68 (EV-D68), Heterogeneous Nuclear Ribonucleoprotein D (HNRNPD AUF1), Endoplasmic Reticulum Protein 57 (ERp57), Progranulin (PGRN), downstream factors such Meiotic Recombination Spo11 (Spo11), AMP-Activated Kinase (AMPK), Double-Strand-Break Repair Rad21 Homolog (Rad21L), IκB (IKK), TDP-43. Conclusion: neurodegeneration, which, phosphorylation, EV-d68, HNRNPD.

Language: Английский

Citations

0