Dysfunctional mTORC1 Signaling: A Convergent Mechanism between Syndromic and Nonsyndromic Forms of Autism Spectrum Disorder?

Magdalon, Juliana; Sánchez-Sánchez, Sandra M; Griesi-Oliveira, Karina; Sertié, Andréa L.

doi:10.3390/ijms18030659

Cited by 44 publications

(34 citation statements)

References 274 publications

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“…). This notion is supported by evidence that neurological disorders such as autism spectrum disorders are associated with dysfunctional mTOR signaling and represent an early pathological marker and a promising therapeutic target . For example, decreased mTOR signaling is detected in the brain of an animal model of Rett syndrome before the manifestation of neurological signs of the disease .…”

Section: Discussionmentioning

confidence: 91%

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities

et al. 2017

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Glaucoma represents a group of multifactorial diseases with a unifying pathology of progressive retinal ganglion cell (RGC) degeneration, causing irreversible vision loss. To test the hypothesis that RGCs are intrinsically vulnerable in glaucoma, we have developed an in vitro model using the SIX6 risk allele carrying glaucoma patient-specific induced pluripotent stem cells (iPSCs) for generating functional RGCs. Here, we demonstrate that the efficiency of RGC generation by SIX6 risk allele iPSCs is significantly lower than iPSCs-derived from healthy, age- and sex-matched controls. The decrease in the number of RGC generation is accompanied by repressed developmental expression of RGC regulatory genes. The SIX6 risk allele RGCs display short and simple neurites, reduced expression of guidance molecules, and immature electrophysiological signature. In addition, these cells have higher expression of glaucoma-associated genes, CDKN2A and CDKN2B, suggesting an early onset of the disease phenotype. Consistent with the developmental abnormalities, the SIX6 risk allele RGCs display global dysregulation of genes which map on developmentally relevant biological processes for RGC differentiation and signaling pathways such as mammalian target of rapamycin that integrate diverse functions for differentiation, metabolism, and survival. The results suggest that SIX6 influences different stages of RGC differentiation and their survival; therefore, alteration in SIX6 function due to the risk allele may lead to cellular and molecular abnormalities. These abnormalities, if carried into adulthood, may make RGCs vulnerable in glaucoma. Stem Cells 2017;35:2239-2252.

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Section: Discussionmentioning

confidence: 91%

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities

et al. 2017

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“…All these changes, together with the enrichment of the mTORC2 downstream signalling pathway, suggest that abnormal expression of PARK7 and GAP-43 might be a result of the dysregulation of the mTOR pathway in the PPS model. Indeed, the mTOR pathway has been shown to be involved in many neurological disorders, such as autism spectrum disorders 47,48 , Alzheimer's disease, tuberous sclerosis complex 46,49,50 , focal cortical dysplasia 51,52 and, more recently, intractable epilepsy 49,[53][54][55][56][57][58] . The mTORC1 and mTORC2 complexes are also upregulated in tissue from patients with MTLE 59 .…”

Section: Discussionmentioning

confidence: 99%

Laser microdissection-based microproteomics of the hippocampus of a rat epilepsy model reveals regional differences in protein abundances

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Vieira

Matos

et al. 2020

Sci Rep

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cendes 8,9 & iscia Lopes-cendes 1,9* Mesial temporal lobe epilepsy (MTLE) is a chronic neurological disorder affecting almost 40% of adult patients with epilepsy. Hippocampal sclerosis (HS) is a common histopathological abnormality found in patients with MTLE. HS is characterised by extensive neuronal loss in different hippocampus subregions. In this study, we used laser microdissection-based microproteomics to determine the protein abundances in different regions and layers of the hippocampus dentate gyrus (DG) in an electric stimulation rodent model which displays classical HS damage similar to that found in patients with MTLE. Our results indicate that there are differences in the proteomic profiles of different layers (granule cell and molecular), as well as different regions, of the DG (ventral and dorsal). We have identified new signalling pathways and proteins present in specific layers and regions of the DG, such as PARK7, RACK1, and connexin 31/gap junction. We also found two major signalling pathways that are common to all layers and regions: inflammation and energy metabolism. Finally, our results highlight the utility of high-throughput microproteomics and spatial-limited isolation of tissues in the study of complex disorders to fully appreciate the large biological heterogeneity present in different cell populations within the central nervous system. Currently, it is well recognised that proteins and their biological roles are multifaceted and complex since all biological mechanisms rely on correct protein function. However, a major part of protein cellular machinery remains unknown, especially in disease-related processes. Therefore, studying proteins, specifically their presence and abundance, is relevant when addressing complex mechanisms leading to disease 1. Laser microdissection-based microproteomics allows for the study of the proteome of enriched specific cell types of interest obtained from a small amount of tissue (100 μg or less) 1-3. Epilepsy is a chronic neurological disorder affecting around 2% of the world population 27/02/2020 18:22:00. It presents a wide variety of clinic manifestations, aetiologies, severities, and prognoses. However, the occurrence of an epileptic seizure, caused by abnormal neuronal discharges, is the common feature of all types of epilepsy 4. Mesial temporal lobe epilepsy (MTLE) is the most frequent form in adults, present in 40% of patients with epilepsy, many of whom do not respond to clinical treatment 5-8 .

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“…Studying rare mutations has proven to be valuable in identifying common pathways implicated in autism (Berg and Geschwind 2012;Willsey et al 2013). Our work has connected RAB39b mutation-associated macrocephaly/autism with PI3K-AKT-mTOR signaling, a convergent pathway implicated in ASD pathology across divergent etiologies (Huber et al 2015;Magdalon et al 2017). RAB39b interacts with PI3K components p85α and p110α, and its deletion promotes PI3K-AKT-mTOR signaling activity in human NPCs, cerebral organoids, and mouse cortex.…”

Section: Early Neurodevelopmental Dysregulation In Macrocephaly/autismentioning

confidence: 95%

Cerebral organoid and mouse models reveal a RAB39b–PI3K–mTOR pathway-dependent dysregulation of cortical development leading to macrocephaly/autism phenotypes

et al. 2020

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Dysregulation of early neurodevelopment is implicated in macrocephaly/autism disorders. However, the mechanism underlying this dysregulation, particularly in human cells, remains poorly understood. Mutations in the small GTPase gene RAB39b are associated with X-linked macrocephaly, autism spectrum disorder (ASD), and intellectual disability. The in vivo roles of RAB39b in the brain remain unknown. We generated Rab39b knockout (KO) mice and found that they exhibited cortical neurogenesis impairment, macrocephaly, and hallmark ASD behaviors, which resembled patient phenotypes. We also produced mutant human cerebral organoids that were substantially enlarged due to the overproliferation and impaired differentiation of neural progenitor cells (NPCs), which resemble neurodevelopmental deficits in KO mice. Mechanistic studies reveal that RAB39b interacts with PI3K components and its deletion promotes PI3K-AKT-mTOR signaling in NPCs of mouse cortex and cerebral organoids. The mTOR activity is robustly enhanced in mutant outer radial glia cells (oRGs), a subtype of NPCs barely detectable in rodents but abundant in human brains. Inhibition of AKT signaling rescued enlarged organoid sizes and NPC overproliferation caused by RAB39b mutations. Therefore, RAB39b mutation promotes PI3K-AKT-mTOR activity and alters cortical neurogenesis, leading to macrocephaly and autistic-like behaviors. Our studies provide new insights into neurodevelopmental dysregulation and common pathways associated with ASD across species.

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Dysfunctional mTORC1 Signaling: A Convergent Mechanism between Syndromic and Nonsyndromic Forms of Autism Spectrum Disorder?

Cited by 44 publications

References 274 publications

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities

Laser microdissection-based microproteomics of the hippocampus of a rat epilepsy model reveals regional differences in protein abundances

Cerebral organoid and mouse models reveal a RAB39b–PI3K–mTOR pathway-dependent dysregulation of cortical development leading to macrocephaly/autism phenotypes

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