Details

Autor(en) / Beteiligte

• Yi, Jason J.
• Berrios, Janet
• Newbern, Jason M.
• Snider, William D.
• Philpot, Benjamin D.
• Hahn, Klaus M.
• Zylka, Mark J.

Titel

An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A

Ist Teil von

• Cell, 2015-08, Vol.162 (4), p.795-807

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• Deletion of UBE3A causes the neurodevelopmental disorder Angelman syndrome (AS), while duplication or triplication of UBE3A is linked to autism. These genetic findings suggest that the ubiquitin ligase activity of UBE3A must be tightly maintained to promote normal brain development. Here, we found that protein kinase A (PKA) phosphorylates UBE3A in a region outside of the catalytic domain at residue T485 and inhibits UBE3A activity toward itself and other substrates. A de novo autism-linked missense mutation disrupts this phosphorylation site, causing enhanced UBE3A activity in vitro, enhanced substrate turnover in patient-derived cells, and excessive dendritic spine development in the brain. Our study identifies PKA as an upstream regulator of UBE3A activity and shows that an autism-linked mutation disrupts this phosphorylation control. Moreover, our findings implicate excessive UBE3A activity and the resulting synaptic dysfunction to autism pathogenesis. [Display omitted] •PKA phosphorylates UBE3A at T485 and inhibits UBE3A ubiquitin ligase activity•Autism-linked UBE3A T485A missense mutation disrupts phosphorylation regulation•The T485A mutation hyperactivates UBE3A and increases synapse formation in vivo An autism-linked mutation disrupts the phosphorylation regulation of UBE3A by protein kinase A, leading to enhanced UBE3A activity and excessive dendritic spine development in the brain that might be related to autism pathogenesis.