Directly Converted Neurons as a Novel Cellular Model for ALS and FTD

Modeling human adult-onset neurodegenerative diseases has been historically difficult, with current induced pluripotent stem cell (iPSC) models often showing mild phenotypes. While iPSC systems capture disease-associated genetic variants, generating these cells erases cellular age – a critical component of many

neurodegenerative diseases. An alternative approach is the direct conversion of fibroblasts into neurons, which preserves the epigenetic age of the starting cells. As such, this approach has been highly successful in modeling pathologies of various neurodegenerative diseases including tauopathies, Huntington’s disease, and Alzheimer’s

disease. In the proposed research project, we will employ direct neuronal conversion as a new tool to investigate amyotrophic lateral sclerosis (ALS) and associated frontotemporal dementia (FTD). We will initially study familial ALS cells that have been converted into induced motor neurons and subsequently probe for neurodegenerative

phenotypes. We have already observed stress-induced degeneration in the context of multiple ALS-associated mutations. Removal of epigenetic age via iPSC conversion and antisense oligonucleotide knockdown of mutant proteins will establish the specificity of this system. We will further expand our studies to sporadic ALS lines,

investigating neurodegeneration-associated features including nuclear pore deficits. Finally, cells from ALS/FTD patients will be converted into a cortical identity to provide a novel model for FTD. With these models, we can interrogate disease mechanisms in ALS/FTD. Further, the development of a tractable, patient-derived in vitro

model of familial and sporadic ALS would represent a considerable breakthrough for the ALS research community, facilitating the eventual development of novel therapeutic agents.