Mutations in the Intellectual Disability Gene Ube2a Cause Neuronal Dysfunction and Impair Parkin-Dependent Mitophagy

• Published in: Molecular cell Vol. 50; no. 6; pp. 831 - 843
• Main Authors: Haddad, Dominik M., Vilain, Sven, Vos, Melissa, Esposito, Giovanni, Matta, Samer, Kalscheuer, Vera M., Craessaerts, Katleen, Leyssen, Maarten, Nascimento, Rafaella M.P., Vianna-Morgante, Angela M., De Strooper, Bart, Van Esch, Hilde, Morais, Vanessa A., Verstreken, Patrik
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.06.2013
• Subjects: Adolescent; Adult; Animals; Carbonyl Cyanide m-Chlorophenyl Hydrazone - pharmacology; Case-Control Studies; Cell Line; Child; Drosophila; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Exome; Genetic Association Studies; Humans; Kinetics; Male; Membrane Potential, Mitochondrial; Mental Retardation, X-Linked - genetics; Mice; Mice, Knockout; Mitochondria, Muscle - drug effects; Mitochondria, Muscle - physiology; Mitochondrial Degradation; Mutation, Missense; Neuromuscular Junction - metabolism; Pedigree; Sequence Analysis, DNA; Ubiquitin-Conjugating Enzymes - genetics; Ubiquitin-Conjugating Enzymes - metabolism; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Uncoupling Agents - pharmacology
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2013.04.012

The prevalence of intellectual disability is around 3%; however, the etiology of the disease remains unclear in most cases. We identified a series of patients with X-linked intellectual disability presenting mutations in the Rad6a (Ube2a) gene, which encodes for an E2 ubiquitin-conjugating enzyme. Drosophila deficient for dRad6 display defective synaptic function as a consequence of mitochondrial failure. Similarly, mouse mRad6a (Ube2a) knockout and patient-derived hRad6a (Ube2a) mutant cells show defective mitochondria. Using in vitro and in vivo ubiquitination assays, we show that RAD6A acts as an E2 ubiquitin-conjugating enzyme that, in combination with an E3 ubiquitin ligase such as Parkin, ubiquitinates mitochondrial proteins to facilitate the clearance of dysfunctional mitochondria in cells. Hence, we identify RAD6A as a regulator of Parkin-dependent mitophagy and establish a critical role for RAD6A in maintaining neuronal function. [Display omitted] •ID gene Rad6a identified in exome sequencing in human and synaptic screen in flies•Reduced synaptic transmission in dRad6 mutants because of mitochondrial failure•The E2 RAD6A is required for mitochondrial protein ubiquitination and mitophagy•RAD6A acts with an E3 ligase such as Parkin to induce mitophagy