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Synaptic protein S-palmitoylation as a novel mechanism underlying sex-dependent differences in neuronal plasticity

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 and activity, synapse molecular organization, synaptic plasticity, and molecular signalling pathways. Among different processes assuring proper synapse function are posttranslational modifications, and among them, S-palmitoylation emerges as a crucial mechanism underlying synaptic integrity. Protein S-palmitoylation (S-PALM) refers to the covalent attachment of palmitic acid (C16:0) to cysteine residue(s) via the formation of a thioester bond. Protein S-PALM is governed by a family of PATs, also known as DHHC proteins. Here we focused on the sex-related functional importance of DHHC7 acyltransferase. Under physiological conditions, DHHC7 emerges of particular interest because it palmitoylates various synaptic proteins involved in the regulation of cellular polarity and proliferation as well as in stress and anxiety-related pathology. Moreover, DHHC7 is responsible for S-PALM of sex steroid receptors. Functionally, S-PALM of these receptors regulates their trafficking to the plasma membrane as well as their rapid responses to sex steroid hormones. Using mass spectrometry-based method PANIMoni we identified sex-dependent differences in the S-palmitoylation of synaptic proteins, potentially involved in the regulation of passive membrane properties and excitability (e.g. potassium voltage-gated channels), synaptic transmission (e.g. subunits of glutamate or kainate receptors, voltage-dependent calcium channels) as well as signalling proteins involved in structural plasticity of dendritic spines (e.g. G-proteins and Rab GTPase). Furthermore, to determine a mechanistic source for sex-dependent changes in protein S-palmitoylation we used synaptoneurosomes from DHHC-7 knock-out -/- (DHHC7 KO) female and male mice. Our data showed sex-dependent action of DHHC-7 acyltransferase. Such discovery will facilitate the development of novel and targeted treatments congruous with biological sex.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Monika Zareba-Koziol

LAB HEAD: Jakub Włodarczyk

PROVIDER: PXD025286 | Pride | 2021-06-23

REPOSITORIES: Pride

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Project description:In Alzheimer's disease (AD), early deficits in learning and memory are a consequence of synaptic modification which are likely induced by toxic beta-amyloid oligomers (dAbeta). To identify molecular targets downstream of dAbeta binding we prepared synaptoneurosomes from frontal cortex of control and IAD patients, and isolated mRNAs for comparison of gene expression. This approach elevated synaptic mRNAs above the threshold necessary for expression changes to be discriminated and also reduced other cellular mRNAs. In patients with minimal cognitive impairment (MCI) termed incipient AD (IAD) global measures of cognition declined with increasing levels of dimeric beta (dAbeta). These patients also showed increased expression of neuroplasticity related genes, many encoding 3' UTR consensus sequences that regulate local translation in the synapse. One such gene, GluR2, displayed elevated mRNA and protein expression in IAD. Other neurotransmitter-related genes were also upregulated. Overexpressed genes may induce compensatory as well as negative effects on cognition and provide targets for intervention to moderate the response to dAbeta. Experiment Overall Design: Patient information Experiment Overall Design: CNS tissues were obtained from the USC Alzheimer's Disease Research Center (ADRC) Neuropathology Core, NIA AG05142. Clinical information, including neurological examination, neuropsychological testing such as cognitive assessment, family history, and medications were provided by the USC ADRC Clinical Core. The groups did not differ significantly in age or years of education. Medication histories indicated one IAD patient had used a selective serotonin uptake inhibitor. Post-mortem interval (PMI) ranged from 2 to 9 hours (mean 5.1 hrs.). The study included 8 normal controls and 6 patients with Incipient Alzheimer's Disease. Experiment Overall Design: To augment studies comparing homogenates of control to AD brains, we used synaptoneurosome preparations to enrich for synaptic mRNAs. Synaptoneurosomes were prepared from the prefrontal cortices of control and IAD patients by a simple, rapid, but gentle method using sequential mesh screens.

			Action	DRS
	009111356zar_1M_WT.dat	Other
	009111356zar_1M_WT.raw	Raw
	009111357zar_2M_WT.dat	Other
	009111357zar_2M_WT.raw	Raw
	009111358zar_3M_WT.dat	Other

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Synaptic protein S-palmitoylation as a novel mechanism underlying sex-dependent differences in neuronal plasticity

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