Journal
MOLECULAR CELL
Volume 50, Issue 6, Pages 831-843Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2013.04.012
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Funding
- German Ministry of Education and Research through the MRNET
- Project GENCODYS [241995]
- European Union Framework Program 7 (FP7)
- FWO postdoctoral fellowship
- IWT predoctoral fellowship
- research fund KU Leuven
- Marie Curie Excellence Grant [MEXT-CT-2006-042267]
- ERC Starting Grant [260678]
- Research Foundation Flanders (FWO) [G053913, G079013, G095511, G074709]
- Methusalem grant of the Flemish Government
- Francqui Foundation
- Hercules Foundation [AKUL/09/037]
- Instutuut voor Wetenschap en Technologie (IWT)
- Interuniversity Attraction Pole program by BELSPO [IAP P7/16 NEUROBRAINNET]
- research fund KU Leuven (OT Start) [GOA/13/017]
- PDM postdoctoral fellowship
- VIB
- European Research Council (ERC) [260678] Funding Source: European Research Council (ERC)
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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.
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