Mice lacking the PSD-95-interacting E3 ligase, Dorfin/Rnf19a, display reduced adult neurogenesis, enhanced long-term potentiation, and impaired contextual fear conditioning.

Hanwool Park,Chungwoo Lee,Jinhee Yang,Hyun Kim,Eunjoon Kim,Yeunkum Lee,Yan Li,Jongil Park,Dongmin Lee,Ryunhee Kim

doi:10.1038/srep16410

Abstract

Protein ubiquitination has a significant influence on diverse aspects of neuronal development and function. Dorfin, also known as Rnf19a, is a RING finger E3 ubiquitin ligase implicated in amyotrophic lateral sclerosis and Parkinson’s disease, but its in vivo functions have not been explored. We report here that Dorfin is a novel binding partner of the excitatory postsynaptic scaffolding protein PSD-95. Dorfin-mutant (Dorfin−/−) mice show reduced adult neurogenesis and enhanced long-term potentiation in the hippocampal dentate gyrus, but normal long-term potentiation in the CA1 region. 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. Using a proteomic approach, we also identify a number of proteins whose ubiquitination levels are decreased in the Dorfin−/− brain. These results suggest that Dorfin may regulate adult neurogenesis, synaptic plasticity, and contextual fear memory.

Highlights

Protein ubiquitination in the nervous system regulates different stages of neuronal development, including neurogenesis, migration, neuritogenesis, and synaptogenesis[1,2,3,4,5]
Because Dorfin interacts with postsynaptic density (PSD)-95, an abundant excitatory synaptic scaffolding protein, we explored possible alterations in excitatory synaptic transmission in Dorfin−/− mice
Our study indicates that Dorfin deletion in mice leads to decreased neurogenesis in the dentate gyrus (DG), enhanced long-term potentiation (LTP) in the MPP-DG pathway, and a specific behavioral deficit in contextual fear conditioning, but not in other types of learning and memory

Summary

Introduction

Protein ubiquitination in the nervous system regulates different stages of neuronal development, including neurogenesis, migration, neuritogenesis, and synaptogenesis[1,2,3,4,5]. Ubiquitination of synaptic proteins is thought to regulate diverse aspects of synaptic structure, function, and plasticity. Known substrates of synaptic ubiquitination include scaffolding/adaptor proteins, receptors, and signaling molecules. Dorfin (840 amino acids long in mice) contains two RING domains flanking the in-between ring (IBR) domain, and two transmembrane domains, the precise membrane topology of the protein is not well established. Little is known about the functions of Dorfin in the normal brain, including its protein-protein interactions, substrate proteins, and functional consequences of substrate protein ubiquitination. We found that Dorfin interacts with the abundant excitatory postsynaptic scaffolding protein PSD-95. Dorfin−/− mice show suppressed adult neurogenesis and enhanced long-term potentiation (LTP) in the dentate gyrus (DG) and impaired contextual fear conditioning, suggesting that Dorfin is important for adult neurogenesis, synaptic plasticity, and learning and memory

Methods

Results

Conclusion