Mutations in the intellectual disability gene Ube2a cause neuronal dysfunction 
and impair parkin-dependent mitophagy

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.

doi:10.1016/j.molcel.2013.04.012

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Mutations in the intellectual disability gene Ube2a cause neuronal dysfunction and impair parkin-dependent mitophagy

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Kalscheuer, V. M.
Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Haddad, D. M., Vilain, S., Vos, M., Esposito, G., Matta, S., Kalscheuer, V. M., et al. (2013). Mutations in the intellectual disability gene Ube2a cause neuronal dysfunction and impair parkin-dependent mitophagy. Molecular Cell, 50(6), 831-843. doi:10.1016/j.molcel.2013.04.012.

Cite as: http://hdl.handle.net/11858/00-001M-0000-0018-F302-9

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.