Identification of TDP-43 modifiers through single-cell transcriptional and epigenomic dissection of ALS and FTLD-MND

  • Donnelly, Christopher C.J (PI)
  • Kellis, Manolis M (CoPI)
  • Heiman, Myriam M (CoPI)
  • Belzil, Veronique (CoPI)

Project: Research project

Project Details


Narrative Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two devastating and fatal neurodegenerative disorders that are clinically distinct but show an overlap in genetic factors and central nervous system (CNS) neuropathology in the form of cytoplasmic TDP-43 depositions, but the mechanistic basis of their shared and distinct circuitry remains unknown at the molecular level, preventing the identification of needed therapeutic targets. Here, we use single-cell high-resolution profiling of epigenomic and transcriptional alterations in post-mortem CNS samples from ALS and FTLD with motor neuron disease (FTLD/MND) patients to elucidate their underlying mechanism of action, shed light on their common and distinct circuitry, and identify genetic and cellular factors that drive TDP-43 neuropathology and corresponding neurotoxicity, using patient derived cells and in vivo model systems. This ambitious proposal has the potential to (a) provide mechanistic insights into the development of ALS and FTLD/MND, (b) identify genetic modifiers of TDP-43 pathobiology, and (c) reveal functional risk variants and target genes for therapeutic intervention using gene modifying therapies.
Effective start/end date9/29/218/31/22


  • National Institute of Neurological Disorders and Stroke: $1,817,770.00


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