Altered Expression of Endoplasmic Reticulum Stress-Related Genes in the Middle Frontal Cortex of Subjects with Autism Spectrum Disorder

Crider, Amanda; Ahmed, Anthony O.; Pillai, Anilkumar

doi:10.1159/000477212

Cited by 28 publications

(31 citation statements)

References 47 publications

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“…Mutations in ER-associated genes are known to be involved in some ASD cases. Crider found aberrant expression of ER-stress associated genes IRE1, ATF6, PERK, as well as three others (ATF4, XBP1 and CHOP), in the middle frontal gyrus of ASD subjects post mortem, compared to controls [9]. They also found a correlation between the expression of ER-stress gene expression and the severity of stereotyped ASD behaviors.…”

Section: Cellular Detoxification Deficiency Syndromesmentioning

confidence: 93%

“…Many individuals with ASD exhibit signs of depressed methylation, consistent with homocysteinuria. Increased toxic metal burden is common, and endoplasmic reticulum stress is reported [8,9]. Cortical structures show variation, and, depending on the region of the brain, long-range connections can weaker, or stronger in people with ASDs compared to neurotypicals.…”

Section: Introductionmentioning

confidence: 99%

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Autism is an Acquired Cellular Detoxification Deficiency Syndrome with Heterogeneous Genetic Predisposition

Lw¹

2018

Autism Open Access

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Neurodevelopmental disorders, including autism spectrum disorders, have a complex biological and medical basis involving diverse genetic risk and myriad environmental exposures. Teasing apart the role of specific stressors is made challenging due to the large number of apparently contributing associations, gene x environment interactions and phenomimicry. Historically, these conditions have been rare, making causality assessment at the population level infeasible. Only a few vaccines have been tested for association with autism, and it has been shown that improved diagnosis only explains a percentage of the increase in diagnosis. Now the rates are so high in some countries that public school programs cannot handle to large numbers of special needs students, and professionals are quitting their jobs due to security concerns. Here, I present a mechanistic biomedical process model (theory) of the pathophysiology of autism that reconciles the apparent paradox between the high degree of causal heterogeneity in environmental toxins, the absence of common "autism genes" and the high degree of genetic concordance (heritability) of ASD and ASD-like traits. In brief, the environmental toxin sampling liability for ASD varies among families involving different local exposures following injury to normal cellular endoplasmic detoxification and mitochondrial processes from toxic metals. The literature strongly supports that autism is most accurately seen as an acquired cellular detoxification deficiency syndrome with heterogeneous genetic predisposition that manifests pathophysiologic consequences of accumulated, runaway cellular toxicity. At a more general level, it is a form of a toxicant-induced loss of tolerance of toxins, and of chronic and sustained ER overload ("ER hyperstress"), contributing to neuronal and glial apoptosis via the unfolded protein response (UPR). Inherited risk of impaired cellular detoxification and circulating metal re-toxification in neurons and glial cells accompanied by chronic UPR is key. This model explains the aberrant protein disorder observed in ASD; the great diversity of genes that are found to have low, but real contributions to ASD risk and the sensitivity of individuals with ASD to environmental toxins. The hindrance of detoxification and loss of cellular energetics leads to apoptosis, release of cytokines and chronic neuroinflammation and microglial activation, all observed hallmarks of ASD. Interference with the development of normal complex (redundant) synapses leads to a pathological variation in neuronal differentiation, axon and dendrite outgrowth, and synaptic protein expression. The most general outcomes are overall simplification of gross synaptic anatomy and, neurofunctionally, a loss of inhibitory feedback and aberrations in long-term connections between distant regions of the brain. Failed resolution of the ER stress response leads to redistribution of neurotoxic metals, and the impaired neurocellular processes lead to subsequent accumulation of a variety of additional types o...

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Section: Cellular Detoxification Deficiency Syndromesmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Autism is an Acquired Cellular Detoxification Deficiency Syndrome with Heterogeneous Genetic Predisposition

Lw¹

2018

Autism Open Access

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“…Mutations in the synaptic proteins, neuroligin3, and contactin-associated protein-like 2 (CASPR2), cause retention of these misfolded proteins in the ER that is associated with ASD (Ulbrich et al, 2016 ; Canali et al, 2018 ). Induction of the UPR or its signaling cascades have been linked to pathologies associated with neuropsychiatric and cognitive deficits like memory consolidation defects; ASD; schizophrenia; post-traumatic stress disorders; stress-induced mental disorders; bipolar disorder; and impaired social behavior (Grunebaum et al, 2009 ; Falivelli et al, 2012 ; Di Prisco et al, 2014 ; Ulbrich et al, 2016 ; Wen et al, 2016 ; Crider et al, 2017 ; Dong et al, 2018 ; Shen et al, 2019 ). The precise mechanisms and molecules contributing to the pathophysiology of these neuropsychiatric disorders are incompletely understood.…”

Section: Upr In Neuropsychiatric Disordersmentioning

confidence: 99%

“…The potential role of ATF6 in neuropsychiatric disorders is only emerging (Wen et al, 2016 ; Crider et al, 2017 ). Mutations in CASPR2 associated with the occurrence of ASD causes axonal growth defects in mouse-derived primary cortical neurons (Canali et al, 2018 ).…”

Section: Atf6 Signalingmentioning

confidence: 99%

The Unfolded Protein Response and Autophagy as Drug Targets in Neuropsychiatric Disorders

Srinivasan

Korhonen

Lindholm

2020

Front. Cell. Neurosci.

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Neurons are polarized in structure with a cytoplasmic compartment extending into dendrites and a long axon that terminates at the synapse. The high level of compartmentalization imposes specific challenges for protein quality control in neurons making them vulnerable to disturbances that may lead to neurological dysfunctions including neuropsychiatric diseases. Synapse and dendrites undergo structural modulations regulated by neuronal activity involve key proteins requiring strict control of their turnover rates and degradation pathways. Recent advances in the study of the unfolded protein response (UPR) and autophagy processes have brought novel insights into the specific roles of these processes in neuronal physiology and synaptic signaling. In this review, we highlight recent data and concepts about UPR and autophagy in neuropsychiatric disorders and synaptic plasticity including a brief outline of possible therapeutic approaches to influence UPR and autophagy signaling in these diseases.

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“…Although the underlying neurobiological mechanisms are not well understood, various genetic as well as epigenetic factors have been shown to play critical roles in social behaviors [2]. Recently, accumulating data have implicated disruption of endoplasmic reticulum (ER) homeostasis, or ER stress, in the pathophysiology of the above disorders [3–7].…”

Section: Introductionmentioning

confidence: 99%

Transglutaminase 2 Induces Deficits in Social Behavior in Mice

et al. 2018

Self Cite

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Impairments in social behavior are highly implicated in many neuropsychiatric disorders. Recent studies indicate a role for endoplasmic reticulum (ER) stress in altering social behavior, but the underlying mechanism is not known. In the present study, we examined the role of transglutaminase 2 (TG2), a calcium-dependent enzyme known to be induced following ER stress, in social behavior in mice. ER stress induced by tunicamycin administration increased TG2 protein levels in the mouse prefrontal cortex (PFC). PFC-specific inhibition of TG2 attenuated ER stress-induced deficits in social behavior. Conversely, overexpression of TG2 in the PFC resulted in social behavior impairments in mice. In addition, systemic administration of cysteamine, a TG2 inhibitor, attenuated social behavior deficits. Our preliminary findings using postmortem human brain samples found increases in TG2 mRNA and protein levels in the middle frontal gyrus of subjects with autism spectrum disorder. These findings in mice and human postmortem brain samples identify changes in TG2 activity in the possible dysregulation of social behavior.

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Altered Expression of Endoplasmic Reticulum Stress-Related Genes in the Middle Frontal Cortex of Subjects with Autism Spectrum Disorder

Cited by 28 publications

References 47 publications

Autism is an Acquired Cellular Detoxification Deficiency Syndrome with Heterogeneous Genetic Predisposition

Autism is an Acquired Cellular Detoxification Deficiency Syndrome with Heterogeneous Genetic Predisposition

The Unfolded Protein Response and Autophagy as Drug Targets in Neuropsychiatric Disorders

Transglutaminase 2 Induces Deficits in Social Behavior in Mice

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