Haddad, D.M., Vilain, S., Vos, M., Esposito, G., Matta, S., Kalscheuer, V.M., Craessaerts, K., Leyssen, M., Nascimento, R.M., Vianna-Morgante, A.M., De Strooper, B., Van Esch, H., Morais, V.A., Verstreken, P. (2013). Mutations in the intellectual disability gene ube2a cause neuronal dysfunction and impair parkin-dependent mitophagy.  Mol. Cell 50(6): 831--843.

FBrf0221980

Research paper

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.