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

Summary The prevalence of intellectual disabilityis around 3%; however, the etiology of the disease remains unclear in most cases. We identified a series of patients with X-linked intellectual disabilitypresenting 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 ubiquitinationassays, we show that RAD6A acts as an E2 ubiquitin-conjugating enzymethat, in combination with an E3 ubiquitin ligasesuch as Parkin, ubiquitinatesmitochondrial proteins to facilitate the clearance of dysfunctional mitochondria in cells. Hence, we identify RAD6A as a regulator of Parkin-dependent mitophagyand establish a critical role for RAD6A in maintaining neuronal function.