Abstract
Protein ubiquitination is a widespread, multifunctional, posttranslational protein modification, best known for its ability to direct protein degradation via the ubiquitin proteasome system (UPS). Ubiquitination is also reversible, and the human genome encodes over 90 deubiquitinating enzymes (DUBs), many of which appear to target specific subsets of ubiquitinated proteins. This review focuses on the roles of DUBs in neurodevelopmental disorders (NDDs). We present the current genetic evidence connecting 12 DUBs to a range of NDDs and the functional studies implicating at least 19 additional DUBs as candidate NDD genes. We highlight how the study of DUBs in NDDs offers critical insights into the role of protein degradation during brain development. Because one of the major known functions of a DUB is to antagonize the UPS, loss of function of DUB genes has been shown to culminate in loss of abundance of its protein substrates. The identification and study of NDD DUB substrates in the developing brain is revealing that they regulate networks of proteins that themselves are encoded by NDD genes. We describe the new technologies that are enabling the full resolution of DUB protein networks in the developing brain, with the view that this knowledge can direct the development of new therapeutic paradigms. The fact that the abundance of many NDD proteins is regulated by the UPS presents an exciting opportunity to combat NDDs caused by haploinsufficiency, because the loss of abundance of NDD proteins can be potentially rectified by antagonizing their UPS-based degradation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 614-625 |
| Number of pages | 12 |
| Journal | Biological psychiatry |
| Volume | 92 |
| Issue number | 8 |
| DOIs | |
| State | Published - Oct 15 2022 |
Funding
We apologize to the many investigators whose work we could not cite here due to space restrictions. We are thankful for the funding received from Creola Pora with the help of her friends and colleagues. This work was supported by SFARI Explorer Grant 527556 to M. Piper and L. Jolly. L. Jolly is supported by Australian Research Council ARC DE160100620. J. Gecz is supported by the National Health and Medical Research Council of Australia Research Fellowship (1155224). P. Penzes is supported by National Institute of Health grant R01MH107182. We acknowledge communication of data provided by the following resources: Genotype-Tissue Expression (GTEx) Project - supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS (data obtained from the GTEx Portal on 08/01/21: https://gtexportal.org/home/); The Genome Aggregation Database (gnomAD) which is available free of restrictions under the Creative Commons Zero Public Domain Dedication (data obtained from gnomAD V21.1 on 08/01/21: https://gnomad.broadinstitute.org/); The Biological General Repository for Interaction Datasets (BioGRID; data obtained from BioGRID portal V4.4 on 8/01/21 https://thebiogrid.org/); and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database which are freely available under a 'Creative Commons BY 4.0' (data obtained from STRING V11.5 on 08/01/21 (https://string-db.org/). This work was supported by SFARI Explorer Grant 527556 to MP and LAJ. LAJ is supported by the Australian Research Council (Grant No. DE160100620). JG is supported by the National Health and Medical Research Council of Australia Research Fellowship (Grant No. 1155224). PP is supported by the National Institutes of Health (Grant No. R01MH107182). We apologize to the many investigators whose work we could not cite here due to space restrictions. We are thankful for the funding received from Creola Pora with the help of her friends and colleagues. We acknowledge communication of data provided by the following resources: Genotype-Tissue Expression (GTEx) Project, supported by the Common Fund of the Office of the Director of the National Institutes of Health; National Cancer Institute; National Human Genome Research Institute; National Heart, Lung, and Blood Institute; National Institute on Drug Abuse, National Institute of Mental Health, and National Institute of Neurological Disorders and Stroke (data obtained from the GTEx Portal on August 1, 2021: https://gtexportal.org/home/); the Genome Aggregation Database (gnomAD), which is available free of restrictions under the Creative Commons Zero Public-Domain Dedication (data obtained from gnomAD V2.1.1 on August 1, 2021: https://gnomad.broadinstitute.org/); the Biological General Repository for Interaction Datasets (BioGRID; data obtained from BioGRID portal V4.4 on August 1,2021: https://thebiogrid.org/); and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, which are freely available under a Creative Commons BY 4.0 (data obtained from STRING V11.5 on August 1, 2021: https://string-db.org/). LAJ devised and coordinated the review, compiled and analyzed all data, and wrote and revised the manuscript. JG, MP, RS, and PP contributed to the revision of the manuscript. All authors approved the final manuscript. The authors report no biomedical financial interests or potential conflicts of interest.
Keywords
- Brain development
- Deubiquitinating enzyme
- Neurodevelopmental disorder
- Ubiquitin
- Ubiquitin proteasome system
ASJC Scopus subject areas
- Biological Psychiatry