FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade
Pierre De Rossi, Amanda J. Lewis, Johanna Furrer, Laura De Vos, Tomáš Demeter, Aurélie Zbinden, Weijia Zhong, Vera I. Wiersma, Carlo Scialò, Julien Weber, Zhongning Guo, Stefano Scaramuzza, Marta Di Fabrizio, Carolin Böing, Daniel Castaño‐Díez, Ashraf Al‐Amoudi, Manuela Pérez‐Berlanga, Tammaryn Lashley, Henning Stahlberg, Magdalini Polymenidou
Abstract
Morphologically distinct TDP-43 aggregates occur in clinically different FTLD-TDP subtypes, yet the mechanism of their emergence and contribution to clinical heterogeneity are poorly understood. Several lines of evidence suggest that pathological TDP-43 follows a prion-like cascade, but the molecular determinants of this process remain unknown. We use advanced microscopy techniques to compare the seeding properties of pathological FTLD-TDP-A and FTLD-TDP-C aggregates. Upon inoculation of patient-derived aggregates in cells, FTLD-TDP-A seeds amplify in a template-dependent fashion, triggering neoaggregation more efficiently than those extracted from FTLD-TDP-C patients, correlating with the respective disease progression rates. Neoaggregates are sequentially phosphorylated with N-to-C directionality and with subtype-specific timelines. The resulting FTLD-TDP-A neoaggregates are large and contain densely packed fibrils, reminiscent of the pure compacted fibrils present within cytoplasmic inclusions in postmortem brains. In contrast, FTLD-TDP-C dystrophic neurites show less dense fibrils mixed with cellular components, and their respective neoaggregates are small, amorphous protein accumulations. These cellular seeding models replicate aspects of the patient pathological diversity and will be a useful tool in the quest for subtype-specific therapeutics.