TDP-43 is a major protein player in the pathology of amyothropic lateral sclerosis (ALS) through gain of pathogenic function and pathogenesis induced by loss of its normal function, which involves aggregation and fibril formation of TDP-43. The Polymenidou lab and collaborators could now establish a seeding system with recombinant and patient-derived TDP-43 fibrils, and show that these fibrils are internalized by cells and can even spread from cell to cell. This internalization and spreading of TDP-43 fibrils lead to the aggregation of endogenous TDP-43, like in ALS, and loss of function e.g that cryptic splice sites were abundantly used. The seeding model should enable genetic and drug screens. Their findings have been published in the article "Seeded aggregation of TDP-43 induces its loss of function and reveals early pathological signatures" in the journal Neuron.
Highlights
- TDP-43 fibrils internalize into SH-SY5Y cells and spread from seeded to naive cells
- In vitro-obtained and patient-extracted TDP-43 fibrils induce its loss of function
- Seed-induced TDP-43 loss of function reveals known and novel pathological signatures
- This new TDP-43-seeding cellular model is suitable for genetic and drug screenings
Summary
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.
Read the Publication in Neuron (Open Access)
Abstract, figures, highlights and summary from Scialò et al (2025) Neuron published under a CC BY-NC-ND 4.0 license.