Aberrant intraneuronal trafficking of the RNA-editing enzyme ADAR2 is a key pathogenic mechanism in C9orf72-mediated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), a new study published in Acta Neuropathologica suggests. A team led by Rita Sattler at Barrow Neurological Institute (Phoenix, AZ, USA) found that in patients with C9ALS/FTD, ADAR2, which normally resides in the nucleus, was mislocalized to the cytoplasm, leading to alterations in RNA processing in the nucleus.

DNA repeat expansions in C9orf72 are the most common genetic cause of diseases on the ALS–FTD spectrum, and dysfunctional nucleocytoplasmic transport is one of several mechanisms implicated in the pathogenesis of C9ALS/FTD. “We wanted to explore which RNA-processing proteins could be affected by these transport deficits and, given the crucial role of ADAR2 as an RNA-editing enzyme, we chose to focus on this protein for our investigations,” explains Sattler.

The researchers demonstrated cytoplasmic accumulation of ADAR2 in post-mortem CNS tissue and human induced pluripotent stem cell-derived motor neurons (hiPSC-MNs) from patients with C9ALS/FTD. Similar mislocalization of ADAR2 was observed in brain tissue from a mouse model of C9ALS/FTD.

ADAR2 catalyses the conversion of adenosine to inosine in RNA nucleotide sequences — a post-transcriptional modification termed A-to-I editing. Sattler and colleagues used RNA sequencing to analyse A-to-I editing at 408,580 sites in the human transcriptome.

The team found widespread alterations in A-to-I editing, including both hypo-editing and hyper-editing, in CNS tissue and hiPSC-MNs from patients with C9ALS/FTD. The changes were particularly prominent in genes involved in the eukaryotic translation initiation factor 2 (eIF2) pathway, which has an important role in protein translation.

The researchers demonstrated cytoplasmic accumulation of ADAR2 in post-mortem CNS tissue … from patients with C9ALS/FTD

“We are currently investigating the role of RNA-editing aberrations in a number of target genes that were identified in our studies,” says Sattler. “In addition, in our C9ALS/FTD disease models, we are planning to test small-molecule compounds that act as selective inhibitors of nuclear transport, in the hope of preventing cytoplasmic ADAR2 mislocalization, RNA-editing aberrations and, consequently, neurodegenerative disease pathogenesis.”