biostudies-literatureUnknownZhong WSwiss National Science FoundationNINDS NIH HHSFrontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) shows striking clinical and neuropathological heterogeneity, yet a systematic analysis of subtype-specific features and inter-patient variability was missing. We treated human neurons and neuron-like cells with 30 postmortem brain samples and quantified neoaggregate formation, loss of function and changes in the TDP-43 interactome to define determinants of seeding outcomes. Potent FTLD-TDP-A seeds drove a progressive collapse of physiological TDP-43 interactions accompanied by functional loss. Beyond the burden of pathological TDP-43, we identified the fibrillar core of the lysosomal protein TMEM106B as a critical pro-seeding factor. Transient lysosomal injury markedly enhanced neoaggregation and loss of function, likely bbioRxiv : the preprint server for biology2025.12.19.695531https://www.ebi.ac.uk/biostudies/studies/S-EPMC12767511biostudies-literatureLysosomal escape and TMEM106B fibrillar core determine TDP-43 seeding outcomes.PMC12767511320030RM1 NS133601Lim SMHafliger Mde Cecco EPeter MManglunia RLagier-Tourenne CRamesh NWard MZhong WWilkins OGFratta PPolymenidou MScialo CJagannath SGatta BLeu NLurati FRoschitzki BAguzzi APetrucelli LfalseLysosomal escape and TMEM106B fibrillar core determine TDP-43 seeding outcomes.Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) shows striking clinical and neuropathological heterogeneity, yet a systematic analysis of subtype-specific features and inter-patient variability was missing. We treated human neurons and neuron-like cells with 30 postmortem brain samples and quantified neoaggregate formation, loss of function and changes in the TDP-43 interactome to define determinants of seeding outcomes. Potent FTLD-TDP-A seeds drove a progressive collapse of physiological TDP-43 interactions accompanied by functional loss. Beyond the burden of pathological TDP-43, we identified the fibrillar core of the lysosomal protein TMEM106B as a critical pro-seeding factor. Transient lysosomal injury markedly enhanced neoaggregation and loss of function, likely b2025-01-01T00:00:00Z2025 Dec2026-06-04T03:21:44.073Z2026-06-04T03:12:35.103ZS-EPMC127675114149759510.64898/2025.12.19.695531