22.11.2021The Polymenidou group shows that patient-derived pathological TDP-43 triggers de novo aggregation of physiological TDP-43 in host cells

Frontotemporal dementia (FTD) is characterised by frontotemporal lobar degeneration (FTLD) and accumulation of pathological protein aggregates. FTLD-TDP subtypes are characterised by the accumulation and aggregation of the RNA-binding protein TDP-43. Notably, clinically different FTLD-TDP subtypes show morphologically distinct TDP-43 aggregates. However, the mechanism of the emergence of these aggregates and their contribution to clinical heterogeneity are poorly understood. One crucial question is whether pathological TDP-43 follows a prion-like cascade of amplification and template-directed conversion during disease propagation, and if so, which are the molecular determinants of this process. This study used advanced microscopy techniques to compare the seeding properties of pathological aggregates in two FTLD-TDP subtypes to show that pathological TDP-43 triggers template-dependent aggregation and amplification of neoaggregates. These pathological aggregates have different, subtype-specific seeding potency and follow distinct phosphorylation timelines. Moreover, neoaggregates triggered by different subtypes display different aggregation profiles, resembling the original aggregates in patient brains. Thus these cellular seeding models replicate aspects of the patient pathological diversity and will be a useful tool in the quest for subtype-specific therapeutics.

See De Rossi et al., EMBO Rep