Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects.

Authors

Ashok Cheemala
Amy L Kimble
Emily N Burrage
Stephen B Helming
Jordan D Tyburski
Nathan K Leclair
Omar M Omar
Aamir Zuberi, The Jackson LaboratoryFollow
Melissa Murphy
Evan R Jellison
Bo Reese
Xiangyou Hu
Cathleen Lutz, The Jackson LaboratoryFollow
Riqiang Yan
Patrick A Murphy

Document Type

Article

Publication Date

4-18-2025

Original Citation

Cheemala A, Kimble A, Burrage E, Helming S, Tyburski J, Leclair N, Omar O, Zuberi A, Murphy M, Jellison E, Reese B, Hu X, Lutz C, Yan R, Murphy P. Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects. Sci Adv. 2025;11(16):eads0505

Keywords

JMG, Blood-Brain Barrier, DNA-Binding Proteins, Animals, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Mice, Mutation, Humans, Endothelial Cells, Disease Models, Animal, Brain

JAX Source

Sci Adv. 2025;11(16):eads0505

ISSN

2375-2548

PMID

40238886

DOI

https://doi.org/10.1126/sciadv.ads0505

Grant

nindS nS074256 (to R.Y.); and U54 grant U54 Od020351 (to C.M.l.). We recognize contributions from the Jackson laboratory genome technology services for technical assistance and consultation. the Jackson laboratory scientific services are supported, in part, through the national Cancer institute’s Cancer Core grant P30CA034196.

Abstract

Mutations in the TARDBP gene encoding TDP-43 protein are linked to loss of function in neurons and familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We recently identified reduced nuclear TDP-43 in capillary endothelial cells (ECs) of donors with ALS-FTD. Because blood-brain barrier (BBB) permeability increases in ALS-FTD, we postulated that reduced nuclear TDP-43 in ECs might contribute. Here, we show that nuclear TDP-43 is reduced in ECs of mice with an ALS-FTD–associated mutation in TDP-43 (Tardbp^G348C) and that this leads to cell-autonomous loss of junctional complexes and BBB integrity. Targeted excision of TDP-43 in brain ECs recapitulates BBB defects and loss of junctional complexes and ultimately leads to fibrin deposition, gliosis, phospho-Tau accumulation, and impaired memory and social interaction. Transcriptional changes in TDP-43–deficient ECs resemble diseased brain ECs. These data show that nuclear loss of TDP-43 in brain ECs disrupts the BBB and causes hallmarks of FTD.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.