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

Haddad D. M., VILAIN S. P. L., Vos M., Esposito G., Matta S., Kalscheuer V. M., ...More

Molecular Cell, vol.50, no.6, pp.831-843, 2013 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 50 Issue: 6
  • Publication Date: 2013
  • Doi Number: 10.1016/j.molcel.2013.04.012
  • Journal Name: Molecular Cell
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.831-843
  • Istanbul Medipol University Affiliated: Yes


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 invitro and invivo 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. © 2013 Elsevier Inc.