Characterization of mice lacking the E3 ligase Dorfin/Rnf19a

Abstract

The ubiquitin-proteasome system is one of the key mechanisms to degrade mis-folded and aggregated proteins. Ubiquitination has been implicated in the regulation of both neuronal development and synaptic plasticity. Dorfin, also known as Rnf19a, is E3 ubiquitin ligase and has been implicated in neurodegenerative diseases such as Amyotrophic lateral sclerosis and Parkinson’s disease. I here report that Dorfin interacts with PSD-95, an important scaffolding protein at excitatory synapses. $Dorfin^{-/-}$ mice show reduced adult neurogenesis, increased amplitude of miniature excitatory postsynaptic currents, and enhanced long-term potentiation in the hippocampal dentate gyrus. Behaviorally, $Dorfin^{-/-}$ mice show impaired contextual fear conditioning, but normal levels of cued fear conditioning, fear extinction, spatial learning and memory, object recognition memory, spatial working memory, and pattern separation. I also identified several proteins in Dorfin-mutant ($Dorfin^{-/-}$) mice that are less ubiquitinated than those in wild-type mice. These results suggest that Dorfin may regulate adult neurogenesis, synaptic plasticity, and contextual fear memory.