BDNF‐Akt‐Bcl2 antiapoptotic signaling pathway is compromised in the brain of autistic subjects

Sheikh, Ashfaq M.; Malik, Mazhar N.; Wen, Gen; Chauhan, Abha; Chauhan, Ved; Chen, Gong; Liu, Fei; Brown, W. Ted; Li, Xiaohong

doi:10.1002/jnr.22416

Cited by 105 publications

(90 citation statements)

References 29 publications

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“…47,48 Previously, we found that the apoptosis-related proteins Bcl-2, p53, and cathepsin D are altered in both the brain and the lymphoblasts of autistic subjects. 4,32,49 The pathogenesis of autism may involve enhanced apoptosis in the brain and lymphoblasts. It is possible that the down-regulation of FAK-Src activities may contribute to an alteration of apoptosisrelated proteins in autism.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

Wei

Malik

Sheikh

et al. 2011

The American Journal of Pathology

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Recent studies suggest that one of the major pathways to the pathogenesis of autism is reduced cell migration. Focal adhesion kinase (FAK) has an important role in neural migration, dendritic morphological characteristics, axonal branching, and synapse formation. The FAK-Src complex, activated by upstream reelin and integrin ␤1, can initiate a cascade of phosphorylation events to trigger multiple intracellular pathways, including mitogen-activated protein kinaseextracellular signal-regulated kinase and phosphatidylinositol 3-kinase-Akt signaling. In this study, by using B lymphoblasts as a model, we tested whether integrin ␤1 and FAK-Src signaling are abnormally regulated in autism and whether abnormal FAK-Src signaling leads to defects in B-lymphoblast adhesion, migration, proliferation, and IgG production. To our knowledge, for the first time, we show that protein expression levels of both integrin ␤1 and FAK are significantly decreased in autistic lymphoblasts and that Src protein expression and the phosphorylation of an active site (Y416) are also significantly decreased. We also found that lymphoblasts from autistic subjects exhibit significantly decreased migration, increased adhesion properties, and an impaired capacity for IgG production. The overexpression of FAK in autistic lymphoblasts countered the adhesion and migration defects. In addition, we demonstrate that FAK mediates its effect through the activation of Src, phosphatidylinositol 3-kinase-Akt, and mitogen-activated protein kinase signaling cascades and that paxillin is also likely involved in the regulation of adhesion and migration in autistic lymphoblasts. Autism is a severe neurodevelopmental disorder characterized by problems in communication, social skills, and repetitive behavior. Susceptibility to autism is clearly attributable to the interplay of genetic and environmental factors, 1-10 but the etiology of this disorder is unknown and no biomarkers have yet been proved characteristic of autism. Recent research 11 is beginning to depict three major pathways as being potentially involved in the pathogenesis of autism (ie, reduced cell migration, excitatory-inhibitory imbalance, and abnormal synaptogenesis). The reelin protein encoded by the RELN gene plays a pivotal role in neuronal cell migration and the prenatal development of neural connections.12 Reelin has coexpressed with HAR1F, which is a novel RNA gene expressed specifically in Cajal-Retzius neurons in the developing human neocortex from gestational week 7 to 19 (a crucial period for cortical neuron specification and migration). 13 Linkage between RELN and autism is a replicated genetic finding in autism research, and reelin has been reduced in the serum and brain specimens of autistic subjects.14,15 Reelin can act through ␣3␤1 integrins and exert proteolytic activity on extracellular matrix (ECM) proteins, which are crucial for neuronal migration. 16 Most recently, emerging evidence 17 indicates that synaptic cell adhesion pathways are disrupted in some

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Section: Discussionmentioning

confidence: 99%

Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

Wei

Malik

Sheikh

et al. 2011

The American Journal of Pathology

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“…[9][10][11][12] Studies have linked p53 to developmental abnormalities 13 (see also Supplemental Table 5), and regions adjacent to 17p13.1 encoding for proteins with important roles in brain function and neurodevelopment (eg, axonal dynein heavy chain 2 and Na + /K + ATPase subunit β-2) and others have been found to be associated with autism (AU) (eg, ephrin-B3 14 ). Increased p53/Bcl2 protein ratios had been found in brain regions of a small set of autistic subjects [15][16][17] ; however, no characterization of posttranslational modifications or functional status of p53 was undertaken. Neuronal Pten haploinsufficiency in mice results in a sustained Akt activation and decreased p53 protein expression and function (evidenced by downregulation of p53 targets), mitochondrial dysfunction, accumulation of mtDNA deletions, 6 and the occurrence of aberrant social and repetitive behavior associated with AU.…”

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confidence: 99%

Role ofp53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study

Wong¹,

Napoli²,

Krakowiak³

et al. 2016

Pediatrics

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The tumor suppressor p53 responds to a variety of environmental stressors by regulating cell cycle arrest, apoptosis, senescence, DNA repair, bioenergetics and mitochondrial DNA (mtDNA) copy number maintenance. Developmental abnormalities have been reported in p53-deficient mice, and altered p53 and p53-associated pathways in autism (AU). Furthermore, via the Pten-p53 crosstalk, Pten haploinsufficient-mice have autisticlike behavior accompanied by brain mitochondrial dysfunction with accumulation of mtDNA deletions.

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“…p53 values increased by 130% over those in the postmortem parietal cortex blocks of patients with autism [21]. In another report, p53 levels increased by 67.5% and 38% in the superior frontal and cerebellar cortices of patients with autism, respectively [22].Sheikh et al [23] found an increased p53 expression in the Purkinje and granule cells of the cerebella in people with autism compared with age-matched controls. These findings suggest that deranged apoptotic mechanisms involved in the pathogenesis of patients with autism.…”

Section: Apoptotic Factorsmentioning

confidence: 92%

The Role of Thiamine in Autism

Lương¹

2013

AJPN

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Autism spectrum disorders are a group of neuro-developmental conditions characterized by varying degrees of language impairment, including verbal and non-verbal communication, impaired social skill, and repetitive behaviors. In this paper, we review the evidence for an association between autism and thiamine. A relationship between thiamine status and the development of autism has been established, with thiamine supplementation exhibiting a beneficial clinical effect on children with autism. Thiamine may involve in autism via apoptotic factors (transcription factor p53, Bcl-2, and caspase-3), neurotransmitter systems (serotonin, acetylcholine, and glutamate), and oxidative stress (prostaglandins, cyclooxygenase-2, reactive oxygen species, nitric oxide synthase, the reduced form of nicotinamide adenine dinucleotide phosphate, and mitochondrial dysfunction). In addition, thiamine has also been implicated in autism via its effects on basic myelin protein, glycogen synthetase kinase-3β, alpha-1 antitrypsin, and glyoxalase 1. Thiamine may play a role in children with autism. Additional investigation of thiamine in children with autism is needed.

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BDNF‐Akt‐Bcl2 antiapoptotic signaling pathway is compromised in the brain of autistic subjects

Cited by 105 publications

References 29 publications

Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

Role ofp53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study

The Role of Thiamine in Autism

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