title: Mutations in the intellectual disability gene Ube2a cause neuronal dysfunction and impair parkin-dependent mitophagy.
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.
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium.
authors.forename: Dominik M
authors.initials: DM
authors.lastname: Haddad
authors.forename: Sven
authors.initials: S
authors.lastname: Vilain
authors.forename: Melissa
authors.initials: M
authors.lastname: Vos
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.forename: Samer
authors.initials: S
authors.lastname: Matta
authors.forename: Vera M
authors.initials: VM
authors.lastname: Kalscheuer
authors.forename: Katleen
authors.initials: K
authors.lastname: Craessaerts
authors.forename: Maarten
authors.initials: M
authors.lastname: Leyssen
authors.forename: Rafaella M P
authors.initials: RM
authors.lastname: Nascimento
authors.forename: Angela M
authors.initials: AM
authors.lastname: Vianna-Morgante
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Morais
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D016022:Case-Control Studies; D002460:Cell Line; D002648:Child; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D059472:Exome; D056726:Genetic Association Studies; D006801:Humans; D007700:Kinetics; D008297:Male; D053078:Membrane Potential, Mitochondrial; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000502:physiology; D063306:Mitophagy; D020125:Mutation, Missense; D009469:Neuromuscular Junction / Q000378:metabolism; D010375:Pedigree; D017422:Sequence Analysis, DNA; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D029721:Drosophila Proteins; D014475:Uncoupling Agents; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; C471545:UBE2A protein, human; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein