The hnRNPA1 D262V amyotrophic lateral sclerosis (ALS) mutation is linked to mitochondrial dysfunction.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by motor neuron loss and has been genetically linked to mutations in RNA-binding proteins. A mutation D262V in the RNA-binding protein hnRNPA1, found in a subset of ALS patients, causes widespread splicing pattern changes. Cells expressing this hnRNPA1 mutation exhibit aggregation, reduced proliferation, altered stress granules and abnormal neuronal growth. To further elucidate how a single amino acid substitution in a splicing factor might impact cell growth, we employed ribosome profiling to study translational dynamics across the transcriptome in hnRNPA1 mutant cells. Differential ribosome occupancy was observed for a small number of transcripts linked to synaptic organization and GTPase functions, as well as disrupted codon usage and a global stalling of translation. This downregulation of translation coincided with suppression of the mTOR/AKT signaling pathway. RNA splicing changes in transcripts from genes linked to cilia/cell projections, GTPase cycles and glutamate signaling were also observed. Importantly, major mitochondrial dysfunction and mitochondrial fragmentation were found in hnRNPA1 D262V mutant cells. Overall, this study demonstrates how a single amino acid change in an RNA binding protein can contribute to disrupting cell growth and mitochondrial function related to defects linked to neuronal death in ALS.