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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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: https://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.