Deciphering the mechanisms of TDP-43 and FUS/TLS mediated neurotoxicity
Motor neurone diseases
Protein misfolding | RNA-binding proteins | Amyotrophic lateral sclerosis | Neurodegeneration | Prion-like spreading | Frontotemporal lobar degeneration
This proposal aims to understand the neurotoxic mechanisms triggered by the aggregation and functional interruption of TDP-43 and FUS/TLS, two RNA/DNA-binding proteins integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). I plan to use toxic aggregates of TDP-43 and FUS/TLS, either derived from postmortem patient material, or reconstituted in vitro using purified components, to establish a novel ex vivo model for TDP-43- and FUS/TLS-mediated neurodegeneration in mouse organotypic brain and spinal cord slice cultures. With this system, I will determine the neurotoxic pathways triggered by the induced aggregation of TDP-43 and FUS/TLS, using both unbiased high-throughput sequencing transcriptomic analysis and candidate approaches, and will investigate the role of glial cells in the cell-to-cell spreading of aggregation and toxicity. Lastly, I will establish the relevance of the uncovered mechanisms for human disease by testing them in iPS cell-derived human neurons from ALS patients and healthy controls.