Membrane Charge Drives the Aggregation of TDP-43 Pathological Fragments

Topic: Brain proteins, microglia and lab models

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.

@article{corucci2025-40198794,
  author  = {Corucci, Giacomo and Vadukul, Devkee M. and Paracini, Nicoló and Laux, Valérie and Batchu, Krishna Chaithanya and Aprile, Francesco A. and Pastore, Annalisa},
  title   = {{Membrane Charge Drives the Aggregation of TDP-43 Pathological Fragments}},
  journal = {Journal of the American Chemical Society},
  year    = {2025},
  doi     = {10.1021/jacs.5c00594},
  pmid    = {40198794},
  url     = {https://doi.org/10.1021/jacs.5c00594}
}

Key findings

• 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.

Why it matters

In biophysical experiments with a TDP-43 fragment and synthetic membranes, a higher negative lipid charge caused the protein to bind to the bilayer surface and promoted its aggregation. This is early laboratory work on how TDP-43 interacts with membranes, with no treatment, cure or prevention reported.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1021/jacs.5c00594
• PubMed: 40198794
• Original source →
• Free full text: Journal of the American Chemical Society →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Biochemical and biophysical research communications · 2006-10-30 · usefulness score 56/100 · Lewy body dementia
• An update on genetic frontotemporal dementia Journal of neurology · 2019-05-22 · usefulness score 56/100 · Prevention and risk
• Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice The Journal of clinical investigation · 2011-01-04 · usefulness score 52/100 · Lewy body dementia
• Structural determinants of the cellular localization and shuttling of TDP-43 Journal of cell science · 2008-10-28 · usefulness score 51/100 · Lewy body dementia
• Prion-like properties of pathological TDP-43 aggregates from diseased brains Cell reports · 2013-07-03 · usefulness score 51/100 · Lewy body dementia
• Exosome secretion is a key pathway for clearance of pathological TDP-43 Brain : a journal of neurology · 2016-09-27 · usefulness score 50/100 · Lewy body dementia
• Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis Frontiers in molecular neuroscience · 2019-02-14 · usefulness score 50/100 · Lewy body dementia
• TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes Proceedings of the National Academy of Sciences of the United States of America · 2012-02-09 · usefulness score 48/100 · Lewy body dementia

Later studies that cite this one

1 study in the alzhub library lists this one in its references.

• Elucidation of Molecular Mechanisms of Lipid-Altered Cytotoxicity of TDP-43 Fibrils ACS Chemical Neuroscience · 2026-01-29 · usefulness score 38/100 · Brain tissue and pathology

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