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Free keywords:
Adolescent
Adult
Animals
Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology
Case-Control Studies
Cell Line
Child
Drosophila
Drosophila Proteins/genetics/metabolism
Exome
Genetic Association Studies
Humans
Kinetics
Male
Membrane Potential, Mitochondrial
Mental Retardation, X-Linked/*genetics
Mice
Mice, Knockout
Mitochondria, Muscle/drug effects/physiology
*Mitochondrial Degradation
Mutation, Missense
Neuromuscular Junction/metabolism
Pedigree
Sequence Analysis, DNA
Ubiquitin-Conjugating Enzymes/*genetics/metabolism
Ubiquitin-Protein Ligases/*metabolism
Ubiquitination
Uncoupling Agents/pharmacology
Abstract:
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.
