Modifiers of TDP-43 toxicity in stem cell models of ALS/FTD

Intraneuronal inclusions of the protein TDP-43 are the hallmark of the pathology in the majority of patients with amyotrophic lateral sclerosis and in about half of patients with frontotemporal dementia. The steps leading to aggregation of TDP-43 are incompletely understood. In this project, we will use human neurons grown from patient-derived stem cells to study the mechanisms leading to accumulation of TDP43. Preliminary evidence suggests that such neurons accumulate insoluble TDP-43. In this project, the mechanisms leading to the accumulation of insoluble TDP-43 will be studied and modifiers of TDP-43 pathology will be sought for.