Mutations in the Intellectual Disability Gene Ube2a Cause Neuronal Dysfunction and Impair Parkin-Dependent Mitophagy

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• 作者：Dominik?M. Haddad ; Sven Vilain ; Melissa Vos ; Giovanni Esposito ; Samer Matta ; Vera?M. Kalscheuer ; Katleen Craessaerts ; Maarten Leyssen ; Rafaella?M.P. Nascimento ; Angela?M. Vianna-Morgante ; Bart De?Strooper ; Hilde Van?Esch ; Vanessa?A. Morais ; Patrik Verstreken
• 刊名：Molecular Cell
• 出版年：2013
• 出版时间：27 June, 2013
• 年：2013
• 卷：50
• 期：6
• 页码：831-843
• 全文大小：3241 K

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Summary

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 m>Rad6am> (m>Ube2am>) gene, which encodes for an E2 ubiquitin-conjugating enzyme. m>Drosophilam> deficient for m>dRad6m> display defective synaptic function as a consequence of mitochondrial failure. Similarly, mouse m>mRad6am> (m>Ube2am>) knockout and patient-derived m>hRad6am> (m>Ube2am>) 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.