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Molecular Autism

, 8:41

First Online: 01 August 2017Received: 21 September 2016Accepted: 14 June 2017

Abstract

BackgroundTuberous sclerosis complex TSC is a rare monogenic disorder characterized by benign tumors in multiple organs as well as a high prevalence of epilepsy, intellectual disability and autism. TSC is caused by inactivating mutations in the TSC1 or TSC2 genes. Heterozygocity induces hyperactivation of mTOR which can be inhibited by mTOR inhibitors, such as rapamycin, which have proven efficacy in the treatment of TSC-associated symptoms. The aim of the present study was 1 to identify molecular changes associated with social and cognitive deficits in the brain tissue of Tsc1 mice and 2 to investigate the molecular effects of rapamycin treatment, which has been shown to ameliorate genotype-related behavioural deficits.

MethodsMolecular alterations in the frontal cortex and hippocampus of Tsc1 and control mice, with or without rapamycin treatment, were investigated. A quantitative mass spectrometry-based shotgun proteomic approach LC-MS was employed as an unbiased method to detect changes in protein levels. Changes identified in the initial profiling stage were validated using selected reaction monitoring SRM. Protein Set Enrichment Analysis was employed to identify dysregulated pathways.

ResultsLC-MS analysis of Tsc1 mice and controls n = 30 identified 51 proteins changed in frontal cortex and 108 in the hippocampus. Bioinformatic analysis combined with targeted proteomic validation revealed several dysregulated molecular pathways. Using targeted assays, proteomic alterations in the hippocampus validated the pathways -myelination- -dendrite,- and -oxidative stress-, an upregulation of ribosomal proteins and the mTOR kinase. LC-MS analysis was also employed on Tsc1 and wildtype mice n = 34 treated with rapamycin or vehicle. Rapamycin treatment exerted a stronger proteomic effect in Tsc1 mice with significant changes mainly decreased expression in 231 and 106 proteins, respectively. The cellular pathways -oxidative stress- and -apoptosis- were found to be affected in Tsc1 mice and the cellular compartments -myelin sheet- and -neurofilaments- were affected by rapamycin treatment. Thirty-three proteins which were altered in Tsc1 mice were normalized following rapamycin treatment, amongst them oxidative stress related proteins, myelin-specific and ribosomal proteins.

ConclusionsMolecular changes in the Tsc1 mouse brain were more prominent in the hippocampus compared to the frontal cortex. Pathways linked to myelination and oxidative stress response were prominently affected and, at least in part, normalized following rapamycin treatment. The results could aid in the identification of novel drug targets for the treatment of cognitive, social and psychiatric symptoms in autism spectrum disorders. Similar pathways have also been implicated in other psychiatric and neurodegenerative disorders and could imply similar disease processes. Thus, the potential efficacy of mTOR inhibitors warrants further investigation not only for autism spectrum disorders but also for other neuropsychiatric and neurodegenerative diseases.

KeywordsTuberous sclerosis Rapamycin Proteomics SRM Animal model AbbreviationsASDAutism spectrum disorder

LCLiquid chromatography

MBPMyelin basic protein

mTORMammalian target of rapamycin

MYPRMyelin proteolipid protein

NSFVesicle-fusing ATPase

PKCGProtein kinase C gamma

SODCSuperoxide dismutase C

SRMSelected reaction monitoring

TSCTuberous sclerosis complex

TSC1Harmartin

TSC2Tuberin

TSN-2Tetraspanin 2

WtWildtype

Electronic supplementary materialThe online version of this article doi:10.1186-s13229-017-0151-y contains supplementary material, which is available to authorized users.

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Autor: Hendrik Wesseling - Ype Elgersma - Sabine Bahn

Fuente: https://link.springer.com/



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