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

作者：Carlo Scialò, Weijia Zhong, Somanath Jagannath, Oscar G. Wilkins, Davide Caredio, Marián Hruška-Plocháň, Flavio Lurati, Martina Peter, Elena De Cecco, Luigi Celauro, Adriano Aguzzi, Giuseppe Legname, Pietro Fratta, Magdalini Polymenidou · 发表于：Neuron · 年份：2025 · DOI：10.1016/j.neuron.2025.03.008 · 被引用次数：34 · 研究领域：Amyotrophic Lateral Sclerosis Research、Epigenetics and DNA Methylation、Cancer-related gene regulation

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.