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Lysosomal escape and TMEM106B fibrillar core determine TDP-43 seeding outcomes
Weijia Zhong1, Carlo Scialò1, Beatrice Gatta1
1Department of Quantitative Biomedicine, University of Zurich, Zurich, Switzerland.
Abstract:
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 by promoting fibril interactions with native TDP-43. Our work establishes a mechanistic link between TMEM106B and TDP-43 aggregation, identifies lysosomal escape as a key driver of pathology and introduces the strongest model yet for seeded TDP-43 aggregation and loss of function, to enable discovery of disease modifiers.
Insights
Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) pathology is driven by TMEM106B, a lysosomal protein. Lysosomal injury promotes TDP-43 aggregation and cell dysfunction, offering new therapeutic targets.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) exhibits significant heterogeneity.
- A systematic analysis of FTLD-TDP subtype-specific features and inter-patient variability is lacking.
Purpose of the Study:
- To define determinants of TDP-43 seeding outcomes in FTLD-TDP.
- To investigate the role of TMEM106B and lysosomal function in TDP-43 aggregation.
Main Methods:
- Treatment of human neurons and neuron-like cells with postmortem brain samples from 30 FTLD-TDP patients.
- Quantification of neoaggregate formation, loss of function, and TDP-43 interactome changes.
- Induction of transient lysosomal injury to assess its impact on pathology.
Main Results:
- Potent FTLD-TDP-A seeds induced progressive collapse of physiological TDP-43 interactions and functional loss.
- The fibrillar core of TMEM106B was identified as a critical pro-seeding factor.
- Transient lysosomal injury markedly enhanced TDP-43 neoaggregation and loss of function.
Conclusions:
- A mechanistic link between TMEM106B and TDP-43 aggregation in FTLD-TDP is established.
- Lysosomal escape is identified as a key driver of FTLD-TDP pathology.
- A robust model for seeded TDP-43 aggregation and loss of function is presented for disease modifier discovery.
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