NMDA reseptorin stabiliteetti ja USP6 (DUB) deubikitinaasi

Hakusana: Ubiquitylation of PSD-95?
Vastausartikkeli: https://www.ncbi.nlm.nih.gov/pubmed/31841517

PLoS Biol. 2019 Dec 16;17(12):e3000525. doi: 10.1371/journal.pbio.3000525. eCollection 2019 Dec.

The deubiquitinase USP6 affects memory and synaptic plasticity through modulating NMDA receptor stability.

Zeng F¹, Ma X^1,2, Zhu L¹, Xu Q¹, Zeng Y¹, Gao Y¹, Li G¹, Guo T¹, Zhang H¹, Tang X³, Wang Z⁴, Ye Z^1,5, Zheng L⁶, Zhang H¹, Zheng Q¹, Li K¹, Lu J¹, Qi X¹, Luo H¹, Zhang X¹, Wang Z^1,5, Zhou Y⁶, Yao Y⁷, Ke R⁴, Zhou Y⁸, Liu Y³, Sun H¹, Huang T⁹, Shao Z¹, Xu H⁹, Wang X¹.

1

State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.

2

School of Life Sciences, Xinjiang Normal University, Urumqi, China.

3

Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing, China.

4

School of Biomedical Sciences, Huaqiao University, Quanzhou, China.

5

Department of Neurosurgery, the First Affiliated Hospital of Xiamen University, Xiamen, China.

6

Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China.

7

Department of Functional Neurosurgery, Xiamen Humanity Hospital, Xiamen, China.

8

Department of Translational Medicine, School of Medicine, Xiamen University, Xiamen, China.

9

Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America.

Abstract

Ubiquitin-specific protease (USP) 6 is a hominoid deubiquitinating enzyme (DUB) previously implicated in intellectual disability and autism spectrum disorder. Although these findings link USP6 to higher brain function, potential roles for USP6 in cognition have not been investigated. Here, we report that USP6 is highly expressed in induced human neurons and that neuron-specific expression of USP6 enhances learning and memory in a transgenic mouse model. Similarly, USP6 expression regulates N-methyl-D-aspartate-type glutamate receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD)in USP6 transgenic mouse hippocampi. Proteomic characterization of transgenic USP6 mouse cortex reveals attenuated NMDAR ubiquitination, with concomitant elevation in NMDAR expression, stability, and cell surface distribution with USP6 overexpression. USP6 positively modulates GluN1 expression in transfected cells, and USP6 down-regulation impedes focal GluN1 distribution at postsynaptic densities and impairs synaptic function in neurons derived from human embryonic stem cells. Together, these results indicate that USP6 enhances NMDAR stability to promote synaptic function and cognition.

PMID:

31841517

DOI:

10.1371/journal.pbio.3000525