TY - JOUR
T1 - Mutations in the Intellectual Disability Gene Ube2a Cause Neuronal Dysfunction and Impair Parkin-Dependent Mitophagy
AU - Haddad, Dominik M.
AU - Vilain, Sven
AU - Vos, Melissa
AU - Esposito, Giovanni
AU - Matta, Samer
AU - Kalscheuer, Vera M.
AU - Craessaerts, Katleen
AU - Leyssen, Maarten
AU - Nascimento, Rafaella M.P.
AU - Vianna-Morgante, Angela M.
AU - DeStrooper, Bart
AU - VanEsch, Hilde
AU - Morais, Vanessa A.
AU - Verstreken, Patrik
N1 - Funding Information:
We thank the Bloomington and VDRC stock centers; Kyoung Sang Cho, Willy Baarends, and Konstanze Winklhofer for reagents; and Bassem Hassan, Wim Vandenberghe, and members of the Verstreken and De Strooper labs for comments. V.M.K. is financed by a grant of the German Ministry of Education and Research through the MRNET and by the Project GENCODYS (241995), which is funded by the European Union Framework Program 7 (FP7); S.V. and M.L. are supported by an FWO postdoctoral fellowship; and M.V. is supported by an IWT predoctoral fellowship and a PDM postdoctoral fellowship by the research fund KU Leuven. Support to P.V. was provided by a Marie Curie Excellence Grant (MEXT-CT-2006-042267), an ERC Starting Grant (260678), the Research Foundation Flanders (FWO grants G053913, G079013, G095511, and G074709), a Methusalem grant of the Flemish Government, the Francqui Foundation, the Hercules Foundation (AKUL/09/037), the Instutuut voor Wetenschap en Technologie (IWT), the Interuniversity Attraction Pole program by BELSPO (IAP P7/16 NEUROBRAINNET), the research fund KU Leuven (OT Start, GOA/13/017), and VIB.
PY - 2013/6/27
Y1 - 2013/6/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84880807019&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2013.04.012
DO - 10.1016/j.molcel.2013.04.012
M3 - Journal articles
C2 - 23685073
AN - SCOPUS:84880807019
SN - 1097-2765
VL - 50
SP - 831
EP - 843
JO - Molecular Cell
JF - Molecular Cell
IS - 6
ER -
