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Researchers Pinpoint How Mutation Increases Autism Risk

Mark Zylka, Ph.D.
University of North Carolina
NIEHS Grant DP1ES024088

Scientists have identified more than 1,000 gene mutations related to autism but understanding exactly how they work is elusive. An NIEHS grantee and colleagues report how one of these mutations affects a biochemical pathway that leads to changes in the brain.

The researchers used cell and mouse experiments to study a gene mutation tied to overexpression of the UBE3A enzyme, which studies have suggested must be tightly regulated for normal brain development. They discovered that protein kinase A (PKA) normally phosphorylates UBE3A, acting as a master switch to disengage UBE3A from substrates to block its activity. In cells derived from an autism patient, the researchers observed that an autism-linked mutation disrupted this phosphorylation site, leading to enhanced UBE3A activity and excessive development of small protrusions called dendritic spines on neurons in the brain. A higher than normal density of dendritic spines has been linked with autism.

The researchers also created mice with the same mutation and found excessive dendritic spine development that persisted into young adulthood. When they treated neurons with agents that stimulate PKA production, levels of UBE3A decreased. This finding has promising therapeutic implications since drugs already exist to control PKA.

Citation: Yi JJ, Berrios J, Newbern JM, Snider WD, Philpot BD, Hahn KM, Zylka MJ. 2015. An autism-linked mutation disables phosphorylation control of UBE3A. Cell 162(4):795-807.


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