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

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.

Calcium and activity-dependent signaling in the developing cerebral cortex

“…Neurons and glia also display elevated basal calcium in AD mouse models (reviewed by Pchitskaya et al, 2018 ; Verkhratsky, 2019 ), and genes related to increased cytosolic calcium are enriched in patients with heightened risk for sporadic AD ( Heck et al, 2015 ). Intriguingly, calcium- and activity-dependent pathways altered in neurodevelopmental diseases are thought to be affected in AD ( Ivashko-Pachima et al, 2021 ; Mencer et al, 2021 ). Key calcium signaling effectors like DYRK1A ( Table S1 ) are deregulated both in neurodevelopmental disorders and cortices of sporadic AD patients ( Ferrer et al, 2005 ).…”

Mammalian target of rapamycin (mTOR) signaling pathway and traumatic brain injury: A novel insight into targeted therapy

“…Altogether, a vast majority of experimental analyses have demonstrated the overactivation of mTOR signaling in AD models (Figure 1). 64 They also believe that the inhibitors of mTOR signaling can be considered as promising agents to attenuate the symptoms of the disease.…”

“…Altogether, a vast majority of experimental analyses have demonstrated the overactivation of mTOR signaling in AD models (Figure 1). 64 They also believe that the inhibitors of mTOR signaling can be considered as promising agents to attenuate the symptoms of the disease. Since the mTOR, as an autophagy inhibitor, is associated with Aβ and tau protein accumulation, the modulation of mTOR activity can be helpful in the induction of amyloid plaques clearance and the amelioration of Aβ‐induced neurotoxicity and tau neuropathology.…”

Uncharacterized protein c17orf80: a novel interactor of human mitochondrial nucleoids

“…To date, there is no information regarding the molecular function(s) of c17orf80, and clinically significant data are very limited. However, some genetic association studies linked c17orf80 to autism spectrum disorder (Laird and Maertens, 2021; Mencer et al, 2021; Shaath, 2013) as well as pancreatic (Makler and Narayanan, 2017) and prostate cancers (Cheng et al, 2018). Many orphan proteins detected in genetic screens remain uncharacterized, as their molecular functions have not yet been investigated and are generally difficult to predict (Kustatscher et al, 2022).…”