Lysosomal escape and TMEM106B fibrillar core determine TDP-43 seeding outcomes

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.