Spatial Analysis of Aberrant RNA Isoforms in ALS Neuromuscular Organoids

A number of genes associated with ALS, including TDP43 and FUS, have been implicated in RNA regulation, but it is not clear how defects in RNA regulation lead to motor neuron pathogenesis and ALS. This project will combine a novel culture system — 3D human neuromuscular organoids  that model the intact neuromuscular circuitry — with spatial transcriptomics and new long-read sequencing methods to understand the gene expression changes and RNA modifications associated with these ALS genes. This team will also study how these changes impact motor neuron circuits and ultimately, motor neuron death.