Mutations in the intellectual disability gene Ube2a cause neuronal dysfunction and impair parkin-dependent mitophagy.
Mol Cell
; 50(6): 831-43, 2013 Jun 27.
Article
em En
| MEDLINE
| ID: mdl-23685073
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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Deficiência Intelectual Ligada ao Cromossomo X
/
Enzimas de Conjugação de Ubiquitina
/
Ubiquitina-Proteína Ligases
/
Mitofagia
Tipo de estudo:
Observational_studies
/
Risk_factors_studies
Limite:
Adolescent
/
Adult
/
Animals
/
Child
/
Humans
/
Male
Idioma:
En
Revista:
Mol Cell
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Bélgica