The role of the activity-dependent ubiquitin ligase UBE3A in autism

  • Awarded: 2011
  • Award Type: Research
  • Award #: 143255

Loss-of-function mutations in the UBE3A gene give rise to Angelman syndrome, a neurodevelopmental disorder characterized by absence of speech, a happy demeanor, cognitive delay, motor deficits and seizures. Chromosomal alterations in 15q11-13, the region that includes UBE3A, have been linked to autism. UBE3A encodes an enzyme that targets a subset of cellular proteins for degradation. Elevated levels of several neuronal proteins have previously been observed in the absence of UBE3A.

Michael Greenberg and his colleagues at Harvard Medical School set out to determine if misregulation of one these proteins contributes to Angelman syndrome in a well-characterized mouse model of the disorder. They found that genetic reduction in the levels of the activity-regulated cytoskeletal-associated protein ARC/ARG3.1 rescues seizure and seizure-related conditions present in the Angelman mouse model.

These findings suggest that inhibition of ARC function may represent a novel strategy for therapeutic interventions to treataspects of Angelman syndrome and, possibly, autism. Greenberg’s team also conducted a screen to identify new neuronal targets of UBE3A. Further characterization of these factors may yield new insights into the role of UBE3A in neurodevelopment and autism.

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