Increased NMDARs in neurons and glutamine synthetase in astrocytes underlying autistic-like behaviors of Gabrb1−/− mice

Wang, Jing; Gao, Dianshuai; Xiao, Liquan; Lin, Yanmei; Huang, Lang; Chen, Jinfa; Liang, Guanmei; Li, Weiming; Yi, Wenjuan; Lao, Jianpei; Zhang, Bin; Gao, Tianming; Zhong, Ming; Yang, Xinping

doi:10.1016/j.isci.2023.107476

Cited by 5 publications

(1 citation statement)

References 78 publications

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“…Indeed, PIN1 null mice have an increase in spine density [146], a feature that is commonly associated with autism [147]. Upregulation of NMDARs at neuronal synapses, along with increased glutamine synthetase expression in astrocytes, has been linked to autism in a mouse model [148]. NMDAR expression was upregulated in the brain in another mouse model of autism, and the NMDAR antagonist memantine was used to treat their autistic-like behaviors [149].…”

Section: Pin1 Psd-95 the Synapse And Glyphosatementioning

confidence: 99%

Is Autism a PIN1 Deficiency Syndrome? A Proposed Etiological Role for Glyphosate

Seneff,

Kyriakopoulos,

Nigh

2024

Preprint

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Autism is a neurodevelopmental disorder whose prevalence has increased dramatically in the United States over the past two decades. It is characterized by stereotyped behaviors and impairments in social interaction and communication. In this paper, we present evidence that autism can be viewed as a PIN1 deficiency syndrome. PIN1 (Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1) is a peptidylprolyl cis/trans isomerase, and it has widespread influences in biological organisms. Broadly speaking, PIN1 deficiency is linked to many neurodegenerative diseases, whereas PIN1 overexpression is linked to cancer. Death associated protein kinase 1 (DAPK1) strongly inhibits PIN1, and the hormone melatonin inhibits DAPK1. Melatonin deficiency is strongly linked to autism. It has recently been shown that glyphosate exposure to rats inhibits melatonin synthesis due to increased glutamate release from glial cells and increased expression of metabotropic glutamate receptors. Glyphosate's inhibition of melatonin leads to a reduction in PIN1 availability in neurons. In this paper, we show that PIN1 deficiency can explain many of the unique morphological features of autism, including increased dendritic spine density, missing or thin corpus callosum and reduced bone density. We show how PIN1 deficiency disrupts the functioning of powerful high level signaling molecules, such as nuclear factor erythroid 2-related factor 2 (NRF2) and p53. Dysregulation of both of these proteins has been linked to autism. Severe depletion of glutathione in the brain resulting from chronic exposure to oxidative stressors and extracellular glutamate leads to oxidation of the cysteine residue in PIN1, inactivating the protein and further contributing to PIN1 deficiency. Impaired autophagy leads to increased sensitivity of neurons to ferroptosis. Finally, we consider evidence of the potential toxic effects of the mRNA SARS-CoV-2 vaccines in the light of metabolic defects in autism, and we propose that children with autism would be especially sensitive to damage from the vaccines.

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Section: Pin1 Psd-95 the Synapse And Glyphosatementioning

confidence: 99%

Is Autism a PIN1 Deficiency Syndrome? A Proposed Etiological Role for Glyphosate

Seneff,

Kyriakopoulos,

Nigh

2024

Preprint

View full text Add to dashboard Cite

show abstract

The Interplay of Astrocytes and Neurons in Autism Spectrum Disorder

Cano,

Santos,

Beltrão-Braga

2024

Advances in Neurobiology

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Is autism a PIN1 deficiency syndrome? A proposed etiological role for glyphosate

Seneff,

Kyriakopoulos,

Nigh

2024

Journal of Neurochemistry

View full text Add to dashboard Cite

Autism is a neurodevelopmental disorder, the prevalence of which has increased dramatically in the United States over the past two decades. It is characterized by stereotyped behaviors and impairments in social interaction and communication. In this paper, we present evidence that autism can be viewed as a PIN1 deficiency syndrome. Peptidyl‐prolyl cis/trans isomerase, NIMA‐Interacting 1 (PIN1) is a peptidyl‐prolyl cis/trans isomerase, and it has widespread influences in biological organisms. Broadly speaking, PIN1 deficiency is linked to many neurodegenerative diseases, whereas PIN1 over‐expression is linked to cancer. Death‐associated protein kinase 1 (DAPK1) strongly inhibits PIN1, and the hormone melatonin inhibits DAPK1. Melatonin deficiency is strongly linked to autism. It has recently been shown that glyphosate exposure to rats inhibits melatonin synthesis as a result of increased glutamate release from glial cells and increased expression of metabotropic glutamate receptors. Glyphosate's inhibition of melatonin leads to a reduction in PIN1 availability in neurons. In this paper, we show that PIN1 deficiency can explain many of the unique morphological features of autism, including increased dendritic spine density, missing or thin corpus callosum, and reduced bone density. We show how PIN1 deficiency disrupts the functioning of powerful high‐level signaling molecules, such as nuclear factor erythroid 2‐related factor 2 (NRF2) and p53. Dysregulation of both of these proteins has been linked to autism. Severe depletion of glutathione in the brain resulting from chronic exposure to oxidative stressors and extracellular glutamate leads to oxidation of the cysteine residue in PIN1, inactivating the protein and further contributing to PIN1 deficiency. Impaired autophagy leads to increased sensitivity of neurons to ferroptosis. It is imperative that further research be conducted to experimentally validate whether the mechanisms described here take place in response to chronic glyphosate exposure and whether this ultimately leads to autism.image

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Increased NMDARs in neurons and glutamine synthetase in astrocytes underlying autistic-like behaviors of Gabrb1−/− mice

Cited by 5 publications

References 78 publications

Is Autism a PIN1 Deficiency Syndrome? A Proposed Etiological Role for Glyphosate

Is Autism a PIN1 Deficiency Syndrome? A Proposed Etiological Role for Glyphosate

The Interplay of Astrocytes and Neurons in Autism Spectrum Disorder

Is autism a PIN1 deficiency syndrome? A proposed etiological role for glyphosate

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