Project ID NS-MH2023_27


Co Supervisor 1A IoPPN/Basic and Clinical NeuroscienceWebsite

Co Supervisor 1B IoPPN/Basic and Clinical NeuroscienceWebsite

The role of aberrant innate immune activity in the onset of TDP43 proteinopathy

Cytoplasmic accumulation and nuclear depletion of TDP43 are key pathological hallmarks of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) (1). While there is progress in understanding disease progression, the early presymptomatic (prodromal) stages have remained enigmatic. Using novel cell (2) and animal models of TDP43 proteinopathy, we identified an aberrant innate immune response upon prodromal accumulation of TDP43 and hypothesise it drives the progression of affected cells into disease and degeneration.

This project aims to dissect the underlying pathogenic mechanisms using patient-derived induced pluripotent stem cells (iPSCs) and Drosophila models of TDP43 proteinopathy. The students will steer an independent project covering the entire range of tools and techniques in the neurosciences, from stem cells to behaviour.

The overarching objectives are:
Year 1: training in iPSC culture and gene editing to model rare variants linked to ALS-FTD and in using Drosophila to study the consequences of these in vivo.
Year 2: determine the role of peptidoglycan recognition proteins and antimicrobial peptides we found to be affected in our prodromal models of TDP43 proteinopathy.
Year 3: continue objective from year 2 and combine with assessment of rare genetic variants in co-factors regulating innate immunity using available resources including the Project MinE dataset.

The expected findings have the potential to expand the repertoire of rare variants linked to ALS-FTD, improve our understanding of how innate immunity drives disease onset and progression, and identify candidates for therapeutic targeting that can be clinically assessed for the treatment of these devastating, currently incurable diseases.

One representative publication from each co-supervisor:

Tziortzouda P, Van Den Bosch L, Hirth F (2021) Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation. Nat Rev Neurosci 22, 197-208. doi: 10.1038/s41583-021-00431-1

White MA, Kim E, Duffy A, Adalbert R, Phillips BU, Peters OM, Stephenson J, Yang S, Massenzio F, Lin Z, Andrews S, Segonds-Pichon A, Metterville J, Saksida LM, Mead R, Ribchester RR, Barhomi Y, Serre T, Coleman MP, Fallon JR, Bussey TJ, Brown RH Jr, Sreedharan J (2018) TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD. Nat Neurosci 21, 552-563. doi: 10.1038/s41593-018-0113-5.