Mechanisms of IRF2BPL-related Disorders and Identification of a Potential Therapeutic Strategy

NEDAMSS is a recently discovered neurological disorder caused by heterozygous truncations in the intron-less transcriptional regulator, IRF2BPL. Here, we reprogram patient skin fibroblasts to astrocytes and neurons to study mechanisms of this newly described disease. While full-length wild-type IRF2BPL is primarily localized to the nucleus, we find that truncated patient variants sequester the wild-type protein to the cytoplasm and cause aggregation. Moreover, patient astrocytes fail to support neuronal survival in co-culture assays and exhibit aberrant mitochondria and respiratory dysfunction. Treatment with small molecule Copper ATSM rescues neuronal survival and restores mitochondrial function. Importantly, the in vitro findings are recapitulated in vivo, where co-expression of full-length and truncated IRF2BPL in Drosophila results in cytoplasmic accumulation of full-length IRF2BPL. Moreover, flies harboring heterozygous truncations of the IRF2BPL ortholog (Pits) display progressive motor defects that are ameliorated by CuATSM treatment. Our findings provide insights into mechanisms involved in NEDAMSS and reveal a promising treatment for this severe disorder. Induced astrocytes (iAst) from patients and healthy controls were subject to CuATSM treatment and sequenced. Four patients, four healthy controls, treated and untreated samples, three biological and two technical replicates each, 96 RNA-seq libraries in total.