Mutations in the Intellectual Disability Gene Ube2a Cause Neuronal Dysfunction and Impair Parkin-Dependent Mitophagy
2013
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.
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