Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy

Shrestha Sinha Ray; Debdeep Dutta; Cassandra Dennys; Samantha Powers; Florence Roussel; Pawel Lisowski; Petar Glažar; Xiaojin Zhang; Pipasha Biswas; Joseph R Caporale; Nikolaus Rajewsky; Marc Bickle; Nicolas Wein; Hugo J Bellen; Shibi Likhite; Paul C Marcogliese; Kathrin C Meyer

doi:10.1016/j.celrep.2022.111751

Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy

Cell Rep. 2022 Dec 6;41(10):111751. doi: 10.1016/j.celrep.2022.111751.

Authors

Shrestha Sinha Ray¹, Debdeep Dutta², Cassandra Dennys¹, Samantha Powers¹, Florence Roussel¹, Pawel Lisowski³, Petar Glažar⁴, Xiaojin Zhang¹, Pipasha Biswas¹, Joseph R Caporale¹, Nikolaus Rajewsky⁵, Marc Bickle⁶, Nicolas Wein⁷, Hugo J Bellen², Shibi Likhite¹, Paul C Marcogliese², Kathrin C Meyer⁸

Affiliations

¹ Center for Gene Therapy, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
³ The Berlin Institute for Medical Systems Biology (BIMSB), Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; Department of Psychiatry, Charité - Universitätmedizin Berlin, Berlin, Germany; Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Magdalenka, Poland.
⁴ The Berlin Institute for Medical Systems Biology (BIMSB), Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; Max Planck Institute for Molecular Genetics, Berlin, Germany.
⁵ The Berlin Institute for Medical Systems Biology (BIMSB), Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
⁶ Roche Institute for Translational Bioengineering, Basel, Switzerland.
⁷ Center for Gene Therapy, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
⁸ Center for Gene Therapy, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University, Columbus, OH, USA. Electronic address: kathrin.meyer@nationwidechildrens.org.

PMID: 36476864
DOI: 10.1016/j.celrep.2022.111751

Abstract

The recently discovered neurological disorder NEDAMSS is caused by heterozygous truncations in the transcriptional regulator IRF2BPL. Here, we reprogram patient skin fibroblasts to astrocytes and neurons to study mechanisms of this newly described disease. While full-length IRF2BPL primarily localizes to the nucleus, truncated patient variants sequester the wild-type protein to the cytoplasm and cause aggregation. Moreover, patient astrocytes fail to support neuronal survival in coculture and exhibit aberrant mitochondria and respiratory dysfunction. Treatment with the small molecule copper ATSM (CuATSM) 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.

Keywords: CP: Cell biology; CuATSM; Drosophila; EAP1; IRF2BPL; NEDAMSS; Pits; induced astrocytes; mislocalization; neurodegeneration; nonsense mutations.

Publication types

Research Support, Non-U.S. Gov't