Membrane charge drives the aggregation of TDP-43 pathological fragments
Author(s)
Type
Journal Article
Abstract
TDP-43 protein is an RNA-binding protein linked to amyotrophic lateral sclerosis, frontotemporal dementia, and Alzheimer disease. While normally a protein that shuttles between the nucleus and cytoplasm, TDP-43 has recently been found also in extracellular vesicles. These are an important medium for cell–cell communication that allows the transfer of lipids, proteins, and genetic material among cells. An increasing concern in neurodegenerative diseases, however, is the possibility that extracellular vesicles can also provide an effective way to spread misfolded proteins that could “infect” other cells according to a “prion-like” mechanism. To characterize the interaction of TDP-43 with lipid membranes, we carried out a systematic biophysical study using a TDP-43 fragment lacking the first 84 N-terminal residues, called M85, and synthetic model phospholipid membranes. We utilized standard techniques, such as fluorescence and microscopy, complemented by neutron reflectivity measurements. Our results show that lipid charge affects the modality by which M85 interacts with membranes: a higher negative charge induces the protein to bind to the bilayer surface, promoting protein aggregation and decreasing lipid bilayer damage that this interaction causes. Thus, we speculate that the M85-lipid membrane interaction could play an important and previously undefined role in TDP-43-related neurodegenerative diseases.
Date Issued
2025-04-23
Date Acceptance
2025-03-24
Citation
Journal of the American Chemical Society, 2025, 147 (16), pp.13577-13591
ISSN
0002-7863
Publisher
American Chemical Society
Start Page
13577
End Page
13591
Journal / Book Title
Journal of the American Chemical Society
Volume
147
Issue
16
Copyright Statement
Copyright © 2025 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0 .
License URL
Identifier
10.1021/jacs.5c00594
Publication Status
Published
Date Publish Online
2025-04-08