Sleep and circadian rhythm disruption alters the lung transcriptome to predispose to viral infection.

Sleep and circadian rhythm disruption (SCRD), as encountered during shift work, increases the risk of respiratory viral infection including SARS-CoV-2. However, the mechanism(s) underpinning higher rates of respiratory viral infection following SCRD remain poorly characterized. To address this, we investigated the effects of acute sleep deprivation on the mouse lung transcriptome. Here we show that sleep deprivation profoundly alters the transcriptional landscape of the lung, causing the suppression of both innate and adaptive immune systems, disrupting the circadian clock, and activating genes implicated in SARS-CoV-2 replication, thereby generating a lung environment that could promote viral infection and associated disease pathogenesis. Our study provides a mechanistic explanation of how SCRD increases the risk of respiratory viral infections including SARS-CoV-2 and highlights possible therapeutic avenues for the prevention and treatment of respiratory viral infection.

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

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.

Regional Differences in S-Nitrosylation in the Cortex, Striatum, and Hippocampus of Juvenile Male Mice.

Nitric oxide (NO) is a multifunctional neurotransmitter that plays a major role in neuronal and synaptic functions. S-nitrosylation (SNO), the NO-mediated protein posttransitional modification (PTM), is known to regulate physiological and pathological processes in the brain. However, the physiological role in different neuroanatomical brain regions has not been well investigated. To understand the role of SNO in the brain of juvenile WT mice, we used SNOTRAP technology. We mapped the SNO-proteome in three different neuroanatomical regions: cortex, striatum, and hippocampus. By conducting systems biology analysis, we found that the three brain regions share similar biological processes (BP) including biogenesis and developmental processes. Exclusive and different BP and molecular functions were found for each of the regions. Unraveling the BP and signaling mechanisms of SNO in the cortex, striatum, and hippocampus may help to understand the functional differences between the three regions under physiological conditions.