Critical impact of lysine 136 in TDP-43 phase separation, compartmentalization, and aggregation in living vertebrates

TDP-43 is a nuclear RNA-binding protein that undergoes liquid-liquid phase separation (LLPS) and forms insoluble aggregates in neurodegenerative diseases. By studying TDP-43 in living vertebrates, we confirmed that TDP-43 undergoes LLPS and forms dynamic biomolecular condensates in spinal motor neurons. We validated <i>in vivo</i> that interfering with the lysine residue at position 136 altered the phase separation behavior of TDP-43 by reducing cytoplasmic mislocalization and aggregation. These alterations were post-translational modification (PTM) independent, highlighting that residue 136 is a key structural regulator of TDP-43 function. We further established an adeno-associated virus (AAV)-mediated expression approach in mice that confirmed altered nuclear condensation characteristics of lysine-modified TDP-43. These assessments exposed the formation of dynamic nuclear TDP-43 condensates and emphasize the important role of lysine 136 in maintaining TDP-43 function. Altogether, we establish lysine 136 as a molecular regulator for phase separation and TDP-43 aggregation in amyotrophic lateral sclerosis (ALS) in two <i>in vivo</i> platforms.

Authors

Institutions

Publication Details

Journal
iScience
Published
2025-05-27
DOI
https://doi.org/10.1016/j.isci.2025.112761
Citations
6
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
4.84

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Critical impact of lysine 136 in TDP-43 phase separation, compartmentalization, and aggregation in living vertebrates

Rowan A. W. Radford, Cindy Maurel, Andrés Vidal-Itriago, Roger S. Chung et al.
6 citations
iScience
RNA Research and Splicing
4.84
article

Critical impact of lysine 136 in TDP-43 phase separation, compartmentalization, and aggregation in living vertebrates

Rowan A. W. Radford, Cindy Maurel, Andrés Vidal-Itriago, Roger S. Chung, Alison Hogan, Emily K. Don, Marco Morsch, Jessica Merjane, Leszek Lisowski, Tyler Chapman, Natalie M. Scherer, Patrick Vourc’h, Stephen Cull, Luan Luu, Albert Lee
article en
6 citations

Abstract

TDP-43 is a nuclear RNA-binding protein that undergoes liquid-liquid phase separation (LLPS) and forms insoluble aggregates in neurodegenerative diseases. By studying TDP-43 in living vertebrates, we confirmed that TDP-43 undergoes LLPS and forms dynamic biomolecular condensates in spinal motor neurons. We validated <i>in vivo</i> that interfering with the lysine residue at position 136 altered the phase separation behavior of TDP-43 by reducing cytoplasmic mislocalization and aggregation. These alterations were post-translational modification (PTM) independent, highlighting that residue 136 is a key structural regulator of TDP-43 function. We further established an adeno-associated virus (AAV)-mediated expression approach in mice that confirmed altered nuclear condensation characteristics of lysine-modified TDP-43. These assessments exposed the formation of dynamic nuclear TDP-43 condensates and emphasize the important role of lysine 136 in maintaining TDP-43 function. Altogether, we establish lysine 136 as a molecular regulator for phase separation and TDP-43 aggregation in amyotrophic lateral sclerosis (ALS) in two <i>in vivo</i> platforms.

iScienceVol. 28(7)
Université de Tours (FR), National Academy of Medicine (US), The University of Sydney (AU), Children's Medical Research Institute (AU), Inserm (FR), Centre Hospitalier Universitaire de Tours (FR), Macquarie University (AU)
FightMND, Macquarie University, Stichting ALS Nederland, National Institutes of Health, National Institute of Mental Health, National Institute on Drug Abuse, National Institute of Neurological Disorders and Stroke
Zero hunger
Openalex Percentile: Top 5%
RNA Research and Splicing
4.84
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.