Seeded aggregation of TDP-43 induces its loss of function

ABSTRACT: Neurodegeneration in ALS and 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, high-throughput assessment of TDP-43 aggregate uptake, cell-to-cell spreading and loss of function within living cells, while they progress towards pathology. We show that both patient-derived and recombinant TDP-43 pathological aggregates were abundantly internalized in human neuron-like cells, efficiently recruited endogenous TDP-43 and formed cytoplasmic inclusions reminiscent of ALS/FTD pathology. These neoaggregates progressively drove the nuclear egress of TDP-43 leading to its loss of function. Our model demonstrates the link between TDP-43 aggregation and aberrant cryptic splicing and provides new tools to identify genetic or pharmacologic modifiers of each step in the process.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Weijia Zhong  

LAB HEAD: Magdalini Polymenidou

PROVIDER: PXD058981 | Pride | 2025-04-14

REPOSITORIES: Pride