Michael Greenberg, PhD President and Fellows of Harvard College, Harvard Medical School Validation of Arc and Ephexin5 as Novel Therapeutic Targets for the Treatment of Angelman Syndrome
$200,000 – 2-years
While it has been appreciated for some time that loss-of-function mutations in the UBE3A gene are the primary causative factor for Angelman syndrome (AS), the precise mechanisms by which the loss of Ube3A in the nervous system gives rise to the spectrum of cognitive and behavioral features characteristic of this disorder remain unclear. This gap in knowledge has significantly limited the scope of clearly defined therapeutic strategies for AS. Moreover, therapeutic interventions based on the reactivation of mutated genes such as UBE3A have historically proven extremely challenging to implement. Thus, identification of the molecular mechanisms by which the loss of Ube3A function gives rise to the neurophysiological and cognitive dysfunction associated with AS will provide important insight into AS etiology and open new potential therapeutic avenues to combat AS. Dr. Greenberg’s lab has recently identified two neuronal proteins, termed Arc and Ephexin5, that act as downstream targets of Ube3A. In the absence of Ube3A activity, elevated levels of these two proteins accumulate in neurons, and reduction of the levels of these factors in Ube3A-deficient neuronal cultures is sufficient to reverse specific cellular deficits associated with AS. Building on these findings, they plan to determine the extent to which elevated Arc or Ephexin5 expression contributes to the neurophysiological and cognitive dysfunction associated with AS in the context of a well-characterized mouse model of the disorder. Implication of one or more these factors in specific aspects of AS pathology will provide new opportunities for therapeutic intervention.