Abstract

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are progressive diseases of the central nervous system that form a neurodegenerative spectrum. While seemingly diverse in clinical, pathological, and genetic presentations, there is significant overlap between the diseases, particularly in genetic landscapes. Among the most commonly shared genetic alterations in FTD and ALS are TDP-43 pathology and C9orf72 hexanucleotide repeat expansion (C9orf72RE). Increasingly, abnormal cortical and motor neuron excitability is described here, with such disruptions thought to drive early pre-clinical pathology.

I will investigate pathways driving altered cortical excitability by identifying and examining functional consequences of aberrant splicing events in hiPSC-neuronal circuits models with TDP-43 and C9orf72RE patient genotypes. Our approach is advantageous as we will collate previously published datasets to bioinformatically identify promising candidate abnormal splicing events, like those impacting neuronal excitability. Furthermore, I will establish the functional consequences of altered splicing by assessing neural activity in hiPSC-neuronal networks with electrophysiology and imaging methods.

This research will further our understanding of early pathways leading to altered cortical excitability in FTD and ALS. With no cure and limited therapies, exploring early pathological events, such as abnormal tuning of neural activity, could identify new disease biomarkers and targets for early therapeutic intervention.