Dysregulation of the IGF‐I/PI3K/AKT/mTOR signaling pathway in autism spectrum disorders

Расстройства аутистического спектра (РАС) являются сложной группой нейропсихиатрических заболеваний с точки зрения этиопатогенеза. В основе нейрональных нарушений, приводящих к аутистической симптоматике, лежат дисфункции сигнальных путей. Согласно последним исследованиям одним из наиболее значимых сигнальных путей в развитии данной группы заболеваний является кальциевый сигнальный путь. Кальциевая сигнализация тесно связана с такими сигнальными путями, как MAPK-, Wnt-, PI3K/AKT/mTOR-, нарушение в работе которых приводит к нарушениям серотонинергической, дофаминергической, опиоидной, холинергической, глутаматергической, ГАМКергической передачи и влечет за собой эксайтотоксичность за счёт гиперактивации NMDA- и AMPA-рецепторов, повреждение и гибель нейронов. Все эти процессы в нейрональных клетках напрямую связаны с формированием долговременного потенцирования и депрессии, а нарушения в этих клетках приводят к дисфункции базисных психических процессов. С клинической точки зрения кальциевый сигнальный путь может стать одной из основных мишеней для фармакологической коррекции симптоматических проявлений РАС. Очевидно, что дальнейшие исследования на животных моделях и электрофизиологические клинические исследования необходимы для понимания патогенетических особенностей развития РАС, а также какое именно место занимает сигнальный путь Ca 2+ в данных состояниях. Дальнейшие исследования необходимы, для прояснения потенциальной роли сигнализации Ca 2+в изменениях социального или стериотипического поведении пациентов, что является основной обенностью РАС. Autism spectrum disorders (ASDs) are a group of neuropsychiatric diseases with a complex etiopathogenesis. Neuronal disorders leading to autistic symptoms are determined by dysfunction of signaling pathways. Recent studies have demonstrated that the calcium signaling pathway is one of the major significant pathways for this group of disorders. Calcium signaling is closely linked to MAPK-, Wnt-, and PI3K/AKT/mTOR -pathways, which abnormalities lead to dysfunction of serotonergic, dopaminergic, opioidergic, cholinergic, glutamatergic, and GABAergic transmission and result in excitotoxicity due to hyperactivation of NMDA and AMPA receptors and neuronal damage and death. These processes in neuronal cells are associated with formation of long-term potentiation and depression, and disturbances in these cells lead to failure of basic mental processes. From a clinical point of view, the calcium signaling pathway can become one of major targets for the pharmacological treatment of symptomatic ASD. Obviously, further animal studies and electrophysiological human studies are required for understanding pathogenetic mechanisms of ASD and the contribution of Ca 2+ signaling. Future research will clarify a potential role of Ca 2+ signaling in social or stereotypic behavior, which constitutes a main feature of ADS.

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Update on Atypicalities of Central Nervous System in Autism Spectrum Disorder

Brain Sciences ◽

10.3390/brainsci10050309 ◽

2020 ◽

Vol 10 (5) ◽

pp. 309

Author(s):

Ahmad Naqib Shuid ◽

Putri Ayu Jayusman ◽

Nazrun Shuid ◽

Juriza Ismail ◽

Norazlin Kamal Nor ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Central Nervous System ◽

Nervous System ◽

Signaling Pathway ◽

Immune Dysregulation ◽

Autism Spectrum ◽

Mtor Signaling ◽

Spectrum Disorder ◽

Mtor Signaling Pathway ◽

And Function

Autism spectrum disorder (ASD) is a heterogeneous, behaviorally defined, neurodevelopmental disorder that has been modeled as a brain-based disease. The behavioral and cognitive features of ASD are associated with pervasive atypicalities in the central nervous system (CNS). To date, the exact mechanisms underlying the pathophysiology of ASD still remain unknown and there is currently no cure or effective treatment for this disorder. Many publications implicated the association of ASD with inflammation, immune dysregulation, neurotransmission dysfunction, mitochondrial impairment and cell signaling dysregulation. This review attempts to highlight evidence of the major pathophysiology of ASD including abnormalities in the brain structure and function, neuroglial activation and neuroinflammation, glutamatergic neurotransmission, mitochondrial dysfunction and mechanistic target of rapamycin (mTOR) signaling pathway dysregulation. Molecular and cellular factors that contributed to the pathogenesis of ASD and how they may affect the development and function of CNS are compiled in this review. However, findings of published studies have been complicated by the fact that autism is a very heterogeneous disorder; hence, we addressed the limitations that led to discrepancies in the reported findings. This review emphasizes the need for future studies to control study variables such as sample size, gender, age range and intelligence quotient (IQ), all of which that could affect the study measurements. Neuroinflammation or immune dysregulation, microglial activation, genetically linked neurotransmission, mitochondrial dysfunctions and mTOR signaling pathway could be the primary targets for treating and preventing ASD. Further research is required to better understand the molecular causes and how they may contribute to the pathophysiology of ASD.

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Mitochondrial Dysfunction and Its Relationship with mTOR Signaling and Oxidative Damage in Autism Spectrum Disorders

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557515666150324122930 ◽

2015 ◽

Vol 15 (5) ◽

pp. 373-389 ◽

Cited By ~ 16

Author(s):

Kunio Yui ◽

Atsushi Sato ◽

George Imataka

Keyword(s):

Autism Spectrum Disorders ◽

Oxidative Damage ◽

Mitochondrial Dysfunction ◽

Autism Spectrum ◽

Mtor Signaling ◽

Spectrum Disorders

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Do Autism Spectrum and Autoimmune Disorders Share Predisposition Gene Signature Due to mTOR Signaling Pathway Controlling Expression?

International Journal of Molecular Sciences ◽

10.3390/ijms22105248 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5248

Author(s):

Ekaterina A. Trifonova ◽

Alexandra I. Klimenko ◽

Zakhar S. Mustafin ◽

Sergey A. Lashin ◽

Alex V. Kochetov

Keyword(s):

Signaling Pathway ◽

Genetic Heterogeneity ◽

Target Genes ◽

Great Majority ◽

Autism Spectrum ◽

Autoimmune Disorders ◽

Mtor Signaling ◽

Published Data ◽

Mtor Signaling Pathway ◽

Connected Set

Autism spectrum disorder (ASD) is characterized by uncommon genetic heterogeneity and a high heritability concurrently. Most autoimmune disorders (AID), similarly to ASD, are characterized by impressive genetic heterogeneity and heritability. We conducted gene-set analyses and revealed that 584 out of 992 genes (59%) included in a new release of the SFARI Gene database and 439 out of 871 AID-associated genes (50%) could be attributed to one of four groups: 1. FMRP (fragile X mental retardation protein) target genes, 2. mTOR signaling network genes, 3. mTOR-modulated genes, and 4. vitamin D3-sensitive genes. With the exception of FMRP targets, which are obviously associated with the direct involvement of local translation disturbance in the pathological mechanisms of ASD, the remaining categories are represented among AID genes in a very similar percentage as among ASD predisposition genes. Thus, mTOR signaling pathway genes make up 4% of ASD and 3% of AID genes, mTOR-modulated genes—31% of both ASD and AID genes, and vitamin D-sensitive genes—20% of ASD and 23% of AID genes. The network analysis revealed 3124 interactions between 528 out of 729 AID genes for the 0.7 cutoff, so the great majority (up to 67%) of AID genes are related to the mTOR signaling pathway directly or indirectly. Our present research and available published data allow us to hypothesize that both a certain part of ASD and AID comprise a connected set of disorders sharing a common aberrant pathway (mTOR signaling) rather than a vast set of different disorders. Furthermore, an immune subtype of the autism spectrum might be a specific type of autoimmune disorder with an early manifestation of a unique set of predominantly behavioral symptoms.

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Abnormal mTOR Activity in Pediatric Autoimmune Neuropsychiatric and MIA-Associated Autism Spectrum Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms23020967 ◽

2022 ◽

Vol 23 (2) ◽

pp. 967

Author(s):

Ekaterina A. Trifonova ◽

Zakhar S. Mustafin ◽

Sergey A. Lashin ◽

Alex V. Kochetov

Keyword(s):

Autism Spectrum Disorder ◽

Autism Spectrum Disorders ◽

Environmental Factors ◽

Behavioral Problems ◽

Early Onset ◽

Mammalian Target Of Rapamycin ◽

Autism Spectrum ◽

Mtor Signaling ◽

Spectrum Disorders ◽

Mtor Activity

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by the early onset of communication and behavioral problems. ASD is highly heritable; however, environmental factors also play a considerable role in this disorder. A significant part of both syndromic and idiopathic autism cases could be attributed to disorders caused by mammalian target of rapamycin (mTOR)-dependent translation deregulation. This narrative review analyzes both bioinformatic and experimental evidence that connects mTOR signaling to the maternal autoantibody-related (MAR) autism spectrum and autoimmune neuropsychiatric disorders simultaneously. In addition, we reconstruct a network presenting the interactions between the mTOR signaling and eight MAR ASD genes coding for ASD-specific maternal autoantibody target proteins. The research discussed in this review demonstrates novel perspectives and validates the need for a subtyping of ASD on the grounds of pathogenic mechanisms. The utter necessity of designing ELISA-based test panels to identify all antibodies related to autism-like behavior is also considered.

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