Protein Phosphorylation Signaling Cascades in Autism: The Role of mTOR Pathway

Boksha, Irina S.; Прохорова, Т. А.; Tereshkina, Elena B.; Savushkina, Olga K.; Бурбаева, Г. Ш.

doi:10.1134/s0006297921050072

Cited by 10 publications

(11 citation statements)

References 112 publications

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“…Rapamycin has been used for the management of multiple types of cancer, neurodegenerative diseases, including Alzheimer's and Parkinson's, and allograft rejection (19,58,59). In a mouse model of TSC, rapamycin reversed behavioral abnormalities and reduced epileptic activity (56,57). However, the use of more specific drugs, such as those that target p70S6K or RSKs may be better treatment options due to the broad side-effects of mTOR inhibition (60,61).…”

Section: Discussionmentioning

confidence: 99%

Quantitative proteomics and phosphoproteomics of PPP2R5D variants reveal deregulation of RPS6 phosphorylation through converging signaling cascades

Smolen

Papke

Swingle

et al. 2023

Preprint

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Variants in the phosphoprotein phosphatase-2 regulatory protein-5D gene (PPP2R5D) cause the clinical phenotype of Jordan's Syndrome (PPP2R5D-related disorder), which includes intellectual disability, hypotonia, seizures, macrocephaly, autism spectrum disorder and delayed motor skill development. The disorder originates from de novo single nucleotide mutations, generating missense variants that act in a dominant manner. Pathogenic mutations altering 13 different amino acids have been identified, with the E198K variant accounting for ~40% of reported cases. Here, we use CRISPR-PRIME genomic editing to introduce a transition (c.592G>A) in the PPP2R5D allele in a heterozygous manner in HEK293 cells, generating E198K-heterozygous lines to complement existing E420K variant lines. We generate global protein and phosphorylation profiles of wild-type, E198K, and E420K cell lines and find unique and shared changes between variants and wild-type cells in kinase- and phosphatase-controlled signaling cascades. As shared signaling alterations, we observed ribosomal protein S6 (RPS6) hyperphosphorylation, indicative of increased ribosomal protein S6-kinase activity. Rapamycin treatment suppressed RPS6 phosphorylation in both, suggesting activation of mTORC1. Intriguingly, our data suggest AKT-dependent (E420K) and -independent (E198K) activation of mTORC1. Thus, although upstream activation of mTORC1 differs between PPP2R5D-related disorder genotypes, treatment with rapamycin or a p70S6K inhibitor warrants further investigation as potential therapeutic strategies for patients.

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Section: Discussionmentioning

confidence: 99%

Quantitative proteomics and phosphoproteomics of PPP2R5D variants reveal deregulation of RPS6 phosphorylation through converging signaling cascades

Smolen

Papke

Swingle

et al. 2023

Preprint

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“…In fact, microglial dysfunction has been shown to precede major myelin breakdown in hereditary demyelinating disorders (211). These data are highly relevant in the context of ASC which is also characterized by disruptions to mTOR signaling (251,261,262), synaptic pruning (200,263) and myelination (214) leading to cortical hyperconnectivity and the resultant behavioral phenotypes (219,264). Thus, the mitochondrial modulation of neurodevelopment, synaptogenesis and myelination manifests in neurophysiological features that are consistently associated with ELS and are well-established components of ASC etiology.…”

Section: From Mal To Neurophysiology Neurochemistry and Behavior: A M...mentioning

confidence: 96%

A Molecular Framework for Autistic Experiences: Mitochondrial Allostatic Load as A Mediator between Autism and Psychopathology

Mahony¹,

O’Ryan²

2022

Preprint

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Molecular research into Autism Spectrum Conditions (ASC) is undergoing an essential shift towards a biopsychosocial framework that is informed by autistic experiences. In this context, research aims are moving away from correcting external autistic behaviors and towards alleviating internal distress. ASC is associated with high rates of depression, suicidality and comorbid psychopathologies, but the underlying mechanisms that mediate this relationship are poorly understood. Here, we integrate emerging psychosocial characterizations of internal autistic experiences within a molecular framework to yield insight into the prevalence of psychopathology in ASC. We demonstrate that recent conceptualizations of social camouflaging and autistic burnout resonate closely with the accepted definitions for early life stress (ELS) and chronic adolescent stress (CAS). We propose that social camouflaging could be considered a distinct form of ELS that contributes to allostatic load, culminating in a pathophysiological state that is experienced as autistic burnout. Autistic burnout is thought to contribute to psychopathology via both psychosocial and neurophysiological mechanisms, but these remain largely unexplored by molecular researchers. Considering recent insights from converging bodies of work in molecular neuroscience, we discuss the substantial evidence implicating mitochondrial dysfunction in ASC to propose a novel role for mitochondrial allostatic load in the relationship between autism and psychopathology. An interplay between mitochondrial metabolism, neuroimmune and neuroendocrine signaling is increasingly implicated in stress-related psychopathologies and these molecular players are also associated with neurodevelopmental, neurophysiological and neurochemical aspects of ASC etiology. Together, this suggests an increased exposure to, and an underlying molecular susceptibility to, ELS that increases the risk of psychopathology in ASC. This article describes an integrative framework shaped by autistic experiences that highlights novel avenues for future research into molecular mechanisms that affect the quality of life and well-being of autistic individuals. Moreover, this framework emphasizes the need for increased access to diagnosis, accommodations, and resources to improve mental health outcomes in autism.

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“…mTOR, as a signaling "hub" that integrates neuronal activity and a variety of synaptic inputs, is involved in multiple cell biological processes, including protein synthesis, transcription, actin dynamics, neuronal morphology, and autophagy. mTOR contains two structurally and functionally distinct complexes, namely mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) (39). Regulation of synaptic protein synthesis by mTOR depends mainly on the phosphorylation of mTORC1 main downstream effectors eukaryotic initiation factor 4E-binding proteins (4E-BPs) and p70S6 kinases (S6K1 and S6K2) (39), suggesting that mTORC1 activation is necessary for synaptic protein synthesis.…”

Section: Characteristics Of Synaptic Structural Alterations In Asd Br...mentioning

confidence: 99%

Molecular mechanisms of exercise intervention in alleviating the symptoms of autism spectrum disorder: Targeting the structural alterations of synapse

Zong

Dong

et al. 2023

Front. Psychiatry

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Autism spectrum disorder (ASD) is a complex and heterogeneous neurodevelopmental disorder characterized by stereotyped behaviors, specific interests, and impaired social and communication skills. Synapses are fundamental structures for transmitting information between neurons. It has been reported that synaptic deficits, such as the increased or decreased density of synapses, may contribute to the onset of ASD, which affects the synaptic function and neuronal circuits. Therefore, targeting the recovery of the synaptic normal structure and function may be a promising therapeutic strategy to alleviate ASD symptoms. Exercise intervention has been shown to regulate the structural plasticity of synapses and improve ASD symptoms, but the underlying molecular mechanisms require further exploration. In this review, we highlight the characteristics of synaptic structural alterations in the context of ASD and the beneficial effects of an exercise intervention on improving ASD symptoms. Finally, we explore the possible molecular mechanisms of improving ASD symptoms through exercise intervention from the perspective of regulating synaptic structural plasticity, which contributes to further optimizing the related strategies of exercise intervention promoting ASD rehabilitation in future.

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Protein Phosphorylation Signaling Cascades in Autism: The Role of mTOR Pathway

Cited by 10 publications

References 112 publications

Quantitative proteomics and phosphoproteomics of PPP2R5D variants reveal deregulation of RPS6 phosphorylation through converging signaling cascades

Quantitative proteomics and phosphoproteomics of PPP2R5D variants reveal deregulation of RPS6 phosphorylation through converging signaling cascades

A Molecular Framework for Autistic Experiences: Mitochondrial Allostatic Load as A Mediator between Autism and Psychopathology

Molecular mechanisms of exercise intervention in alleviating the symptoms of autism spectrum disorder: Targeting the structural alterations of synapse

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