S-Palmitoylation of Synaptic Proteins as a Novel Mechanism Underlying Sex-Dependent Differences in Neuronal Plasticity.

Monika Zaręba-Kozioł,Evgeni Ponimaskin,Matylda Roszkowska,Izabela Figiel,Subhadip Basu,Jakub Włodarczyk,Krystian Bijata,Franziska E Müller,Anup Kumar Halder,Anna Bartkowiak-Kaczmarek,Paulina Kamińska,Weiqi Zhang

doi:10.3390/ijms22126253

Abstract

Although sex differences in the brain are prevalent, the knowledge about mechanisms underlying sex-related effects on normal and pathological brain functioning is rather poor. It is known that female and male brains differ in size and connectivity. Moreover, those differences are related to neuronal morphology, synaptic plasticity, and molecular signaling pathways. Among different processes assuring proper synapse functions are posttranslational modifications, and among them, S-palmitoylation (S-PALM) emerges as a crucial mechanism regulating synaptic integrity. Protein S-PALM is governed by a family of palmitoyl acyltransferases, also known as DHHC proteins. Here we focused on the sex-related functional importance of DHHC7 acyltransferase because of its S-PALM action over different synaptic proteins as well as sex steroid receptors. Using the mass spectrometry-based PANIMoni method, we identified sex-dependent differences in the S-PALM of synaptic proteins potentially involved in the regulation of membrane excitability and synaptic transmission as well as in the signaling of proteins involved in the structural plasticity of dendritic spines. To determine a mechanistic source for obtained sex-dependent changes in protein S-PALM, we analyzed synaptoneurosomes isolated from DHHC7-/- (DHHC7KO) female and male mice. Our data showed sex-dependent action of DHHC7 acyltransferase. Furthermore, we revealed that different S-PALM proteins control the same biological processes in male and female synapses.

Highlights

To determine a mechanistic source for sex-dependent changes in S-PALM pattern and examine S-PALM role as a crucial intracellular mechanism governing sex-specific variances in synapse structure and function, we studied S-PALM of synaptic proteins in DHHC-7 knock-out mice of both sexes
We used sophisticated proteomics and bioinformatics tools to study sex-dependent differences in biological processes related to protein S-PALM
We focused our research on the sex-dependent functions of one of the enzymes governing the S-PALM, the palmitoyl acyltransferase DHHC7

Summary

Introduction

Synaptic plasticity plays a fundamental role in the brain since it is essential for learning and memory. Changes in synapse strength are expressed at the level of different synaptic proteins (i.e., receptors, cytoskeleton elements, signaling molecules) and translated into structural and functional modifications of neuronal functions. The substantial knowledge of how plastic changes of neurons govern the information processing in the brain comes from the research conducted mainly on the male population [1,2]. Divergent synapse molecular organization [3] and signaling pathways [4,5] together with sex-specific changes in plasticity [6,7] may contribute to sex differences in neuronal function and account for sex-related differences in learning and memory [8], emotional responses [9], fear and anxiety. Females are more vulnerable to develop major depressive disorder [11], while males are at higher risk to suffer from autism spectrum disorder [12]

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Conclusion