Abstract Mutations in the RNA/DNA-binding proteins FUS and TDP-43 cause amyotrophic lateral sclerosis (ALS) with distinct neuropathological features. It is currently unclear how these gene mutations lead to selective motor neuron death and if there are common mechanisms across disease causations. Using single cell RNA sequencing of neurons derived from isogenic induced pluripotent stem cell lines, we demonstrate that motor neurons harbouring FUS P525L or FUS R495X mutations show a 4.9- to 15.5-fold larger transcriptional response than interneurons. About 20% of transcripts were coregulated across FUS mutations in motor neurons and about half of these were caused by FUS gain-of-function. Comparison with TDP-43 M337V motor neurons, identified common mitochondrial dysfunction across gene mutations. Metabolic assessment confirmed a decrease in mitochondrial respiration and ATP turnover in mutant FUS and TARDBP motor neurons and live cell microscopy revealed impaired mitochondrial motility across ALS motor axons. Thus, we have identified early mitochondrial dysfunction in motor neurons shared across ALS-causative mutations, that could have major implications for their survival and which could be targeted therapeutically.

Single cell RNA sequencing in isogenic<i>FUS</i>and<i>TARDBP</i>mutant ALS lines reveals early mitochondrial dysfunction as a common pathway in motor neurons

Single cell RNA sequencing in isogenicFUSandTARDBPmutant ALS lines reveals early mitochondrial dysfunction as a common pathway in motor neurons