Seeded aggregation of TDP-43 induces its loss of function and reveals early pathological signatures

Topic: Brain proteins, microglia and lab models

Neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) results from both gain of toxicity and loss of normal function of the RNA-binding protein TDP-43, but their mechanistic connection remains unclear. Increasing evidence suggests that TDP-43 aggregates act as self-templating seeds, propagating pathology through the central nervous system via a prion-like cascade. We developed a robust TDP-43-seeding platform for quantitative assessment of TDP-43 aggregate uptake, cell-to-cell spreading, and loss of function within living cells, while they progress toward pathology. We show that both patient-derived and recombinant TDP-43 pathological aggregates were abundantly internalized by human neuron-like cells, efficiently recruited endogenous TDP-43, and formed cytoplasmic inclusions reminiscent of ALS/FTD pathology. Combining a fluorescent reporter of TDP-43 function with RNA sequencing and proteomics, we demonstrated aberrant cryptic splicing and a loss-of-function profile resulting from TDP-43-templated aggregation. Our data highlight known and novel pathological signatures in the context of seed-induced TDP-43 loss of function.

@article{scialo2025-40157355,
  author  = {Scialò, Carlo and Zhong, Weijia and Jagannath, Somanath and Wilkins, Oscar G. and Caredio, Davide and Hruška-Plocháň, Marián and Lurati, Flavio and Peter, Martina and others},
  title   = {{Seeded aggregation of TDP-43 induces its loss of function and reveals early pathological signatures}},
  journal = {Neuron},
  year    = {2025},
  doi     = {10.1016/j.neuron.2025.03.008},
  pmid    = {40157355},
  url     = {https://doi.org/10.1016/j.neuron.2025.03.008}
}

Key findings

• Neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) results from both gain of toxicity and loss of normal function of the RNA-binding protein TDP-43, but their mechanistic connection remains unclear.
• Increasing evidence suggests that TDP-43 aggregates act as self-templating seeds, propagating pathology through the central nervous system via a prion-like cascade.
• Combining a fluorescent reporter of TDP-43 function with RNA sequencing and proteomics, we demonstrated aberrant cryptic splicing and a loss-of-function profile resulting from TDP-43-templated aggregation.

Why it matters

Using a cell-based seeding platform, this study showed that TDP-43 aggregates can be taken up by human neuron-like cells, recruit normal TDP-43 and cause loss of function. These are laboratory findings about how pathology may spread, not a treatment or prevention for patients.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.neuron.2025.03.008
• PubMed: 40157355
• Original source →
• Free full text: Zurich Open Repository and Archive (University of Zurich) →

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

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