Proteomics of autism and Alzheimer’s mouse models reveal common alterations in mTOR signaling pathway

Shira Mencer, Maryam Kartawy, Felix Lendenfeld, Huda Soluh, Manish Kumar Tripathi, Igor Khaliulin, Haitham Amal*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Autism spectrum disorder (ASD) and Alzheimer’s disease (AD) are two different neurological disorders that share common clinical features, such as language impairment, executive functions, and motor problems. A genetic convergence has been proposed as well. However, the molecular mechanisms of these pathologies are still not well understood. Protein S-nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modification, targets key proteins implicated in synaptic and neuronal functions. Previously, we have shown that NO and SNO are involved in the InsG3680(+/+) ASD and P301S AD mouse models. Here, we performed large-scale computational biology analysis of the SNO-proteome followed by biochemical validation to decipher the shared mechanisms between the pathologies. This analysis pointed to the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway as one of the shared molecular mechanisms. Activation of mTOR in the cortex of both mouse models was confirmed by western blots that showed increased phosphorylation of RPS6, a major substrate of mTORC1. Other molecular alterations affected by SNO and shared between the two mouse models, such as synaptic-associated processes, PKA signaling, and cytoskeleton-related processes were also detected. This is the first study to decipher the SNO-related shared mechanisms between SHANK3 and MAPT mutations. Understanding the involvement of SNO in neurological disorders and its intersection between ASD and AD might help developing an effective novel therapy for both neuropathologies.

Original languageAmerican English
Article number480
JournalTranslational Psychiatry
Volume11
Issue number1
DOIs
StatePublished - 17 Sep 2021

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© 2021, The Author(s).

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