Angelman syndrome (AS) is a human neurological disorder that is associated with symptoms that include cognitive impairment, motor abnormalities, and epilepsy. In most cases, AS is caused by the deletion of small portions on chromosome 15, which includes the UBE3A gene. The UBE3A gene encodes an enzyme termed ubiquitin ligase E3A (also termed E6-AP), which is one of a family of enzymes that covalently attaches polyubiquitin chains to proteins to signal for their recognition and degradation by the 26S proteasome. A mouse model of AS has been generated and these mice exhibit seizures, impaired motor function, and cognitive deficits that correlate with neurological alterations observed in humans. Hippocampus-dependent learning and memory is impaired in AS model mice, as is long-term potentiation (LTP), a long-lasting form of synaptic plasticity thought to be a cellular substrate for memory. Recently it was reported that AS model mice exhibit mitochondrial dysfunction. Moreover, mitochondria are considered to be one of the primary sources of oxidative stress in cells, and we recently have shown that reduction mitochondrial-derived superoxide can rescue synaptic plasticity and memory impairments in Alzheimer's disease model mice. Taken together, these findings have led us to hypothesize that mitochondrial-derived superoxide contributes to synaptic plasticity and memory impairments in AS model mice. Consistent with this idea, our preliminary data indicate that the levels of mitochondrial superoxide are elevated in the hippocampus of AS mice. Herein, we propose to determine whether reducing levels of mitochondrial-derived superoxide using pharmacological and genetic approaches can 1) rescue hippocampal LTP deficits displayed by AS mice, 2) reverse memory impairments displayed by AS mice, and 3) improve motor performance and reduce audiogenic seizures displayed by AS mice. The results of these studies should provide insight into whether oxidative stress is associated with AS, how it impacts hippocampal synaptic plasticity, hippocampus-dependent memory, and other forms of neurological dysfunction in AS, and whether use of mitochondria-targeted antioxidants could be a viable therapy for treating individuals with AS.

Public Health Relevance

A mouse model of Angelman syndrome (AS) has been generated that exhibits symptoms consistent with the human genetic disorder, including cognitive impairment, motor abnormalities, and epilepsy. We have proposed to determine whether reducing oxidative stress caused by mitochondrial dysfunction can reverse the aforementioned neurological abnormalities in AS model mice. These studies will determine whether reducing mitochondrial-derived oxidative stress is a potential therapy for the treatment of individuals with AS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS078718-02
Application #
8337857
Study Section
Special Emphasis Panel (ZRG1-MDCN-G (03))
Program Officer
Mamounas, Laura
Project Start
2011-09-30
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$192,500
Indirect Cost
$67,500
Name
New York University
Department
Neurology
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
Pick, Joseph E; Wang, Li; Mayfield, Joshua E et al. (2013) Neuronal expression of the ubiquitin E3 ligase APC/C-Cdh1 during development is required for long-term potentiation, behavioral flexibility, and extinction. Neurobiol Learn Mem 100:25-31
Santini, Emanuela; Huynh, Thu N; MacAskill, Andrew F et al. (2013) Exaggerated translation causes synaptic and behavioural aberrations associated with autism. Nature 493:411-5
Kaphzan, Hanoch; Buffington, Shelly A; Ramaraj, Akila B et al. (2013) Genetic reduction of the *1 subunit of Na/K-ATPase corrects multiple hippocampal phenotypes in Angelman syndrome. Cell Rep 4:405-12
Ma, Tao; Trinh, Mimi A; Wexler, Alyse J et al. (2013) Suppression of eIF2* kinases alleviates Alzheimer's disease-related plasticity and memory deficits. Nat Neurosci 16:1299-305