Key result
Proteomic analysis of autism and Alzheimer's mouse models revealed shared alterations in the mTOR signaling pathway, with significantly increased phosphorylation of RPS6 indicating mTORC1 hyperactivation.
Why the study?
Autism spectrum disorder and Alzheimer's disease share clinical features and genetic convergence, but their shared molecular mechanisms are still not well understood.
p-value: p=<0.01
The study identifies shared SNO-related mechanisms, specifically mTORC1 signaling, between ASD and AD mouse models, suggesting potential novel therapeutic targets.
SNO may link ASD-AD pathways; hypothesis-generating and leaves open any shared therapeutic targets.
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.
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Mencer et al. (2021) studied Autism spectrum disorder and Alzheimer's disease (mouse models). Shank3 and P301S mutations (S-nitrosylation proteomic analysis) vs. Wild-type mice was evaluated on Phosphorylation levels of RPS6 (P-RPS6) as a marker of mTORC1 activity (p=<0.01). Proteomic analysis of autism and Alzheimer's mouse models revealed shared alterations in the mTOR signaling pathway, with significantly increased phosphorylation of RPS6 indicating mTORC1 hyperactivation.
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