The role of peptidyl-prolyl isomerase Pin1 in neuronal signaling in epilepsy

Chen, Yu‐Wen; Hou, Xiaorui; Pang, Jing; Yang, Fan; Li, Angcheng; Lin, Sibo; Lin, Na; Lee, Tae Ho; Liu, Hekun

doi:10.3389/fnmol.2022.1006419

Cited by 5 publications

(3 citation statements)

References 166 publications

(224 reference statements)

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“…The balance of PIN1 isomerase activity would therefore be of importance for epilepsy, since it regulates the excitatory glutamate, N-methyl-D-aspartic acid (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and the inhibitory gamma-aminobutyric acid (GABA) and glycine receptors. All these receptors are deregulated during epilepsy, as described in the Y Chen et al study [243].…”

Section: Pin1 and Epilepsymentioning

confidence: 83%

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 and Epilepsymentioning

confidence: 83%

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

Seneff,

Kyriakopoulos,

Nigh

2024

Preprint

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“…In epilepsy, early studies on the role of Pin1, as recently reviewed by Chen and colleagues [225], suggest that Pin1 regulates the stabilities of several disease-related proteins. For example, Pin1 binds and isomerizes protein kinase C, which is tenuously associated with the neurotransmitter balance and neuronal hyperexcitability, subsequently priming it for agonist-induced, ubiquitin-mediated degradation [107,226,227].…”

Section: Pin1-regulated Ubiquitination In Other Neurological Disordersmentioning

confidence: 99%

Pin1-Catalyzed Conformation Changes Regulate Protein Ubiquitination and Degradation

Jeong,

Usman,

et al. 2024

Cells

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The unique prolyl isomerase Pin1 binds to and catalyzes cis–trans conformational changes of specific Ser/Thr-Pro motifs after phosphorylation, thereby playing a pivotal role in regulating the structure and function of its protein substrates. In particular, Pin1 activity regulates the affinity of a substrate for E3 ubiquitin ligases, thereby modulating the turnover of a subset of proteins and coordinating their activities after phosphorylation in both physiological and disease states. In this review, we highlight recent advancements in Pin1-regulated ubiquitination in the context of cancer and neurodegenerative disease. Specifically, Pin1 promotes cancer progression by increasing the stabilities of numerous oncoproteins and decreasing the stabilities of many tumor suppressors. Meanwhile, Pin1 plays a critical role in different neurodegenerative disorders via the regulation of protein turnover. Finally, we propose a novel therapeutic approach wherein the ubiquitin–proteasome system can be leveraged for therapy by targeting pathogenic intracellular targets for TRIM21-dependent degradation using stereospecific antibodies.

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“…195 Not surprisingly, altered PSD-95 function has been implicated in epilepsy. [196][197][198][199] In addition, PSD-95 regulates dendritic morphology, stabilizes dendritic spines, and regulates their morphogenesis. [200][201][202][203][204] PSD-95 plays a critical role in controlling the ratio of E/I synapses with a reduction in PSD-95 levels being sufficient to reduce the E/I ratio.…”

Section: Potential Common Effectorsmentioning

confidence: 99%

Rett and Rett-related disorders: Common mechanisms for shared symptoms?

D’Mello

2023

Exp Biol Med (Maywood)

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Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the methyl-CpG binding protein-2 (MeCP2) gene that is characterized by epilepsy, intellectual disability, autistic features, speech deficits, and sleep and breathing abnormalities. Neurologically, patients with all three disorders display microcephaly, aberrant dendritic morphology, reduced spine density, and an imbalance of excitatory/inhibitory signaling. Loss-of-function mutations in the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1 genes also cause similar behavioral and neurobiological defects and were referred to as congenital or variant Rett syndrome. The relatively recent realization that CDKL5 deficiency disorder (CDD), FOXG1 syndrome, and Rett syndrome are distinct neurodevelopmental disorders with some distinctive features have resulted in separate focus being placed on each disorder with the assumption that distinct molecular mechanisms underlie their pathogenesis. However, given that many of the core symptoms and neurological features are shared, it is likely that the disorders share some critical molecular underpinnings. This review discusses the possibility that deregulation of common molecules in neurons and astrocytes plays a central role in key behavioral and neurological abnormalities in all three disorders. These include KCC2, a chloride transporter, vGlut1, a vesicular glutamate transporter, GluD1, an orphan-glutamate receptor subunit, and PSD-95, a postsynaptic scaffolding protein. We propose that reduced expression or activity of KCC2, vGlut1, PSD-95, and AKT, along with increased expression of GluD1, is involved in the excitatory/inhibitory that represents a key aspect in all three disorders. In addition, astrocyte-derived brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and inflammatory cytokines likely affect the expression and functioning of these molecules resulting in disease-associated abnormalities.

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The role of peptidyl-prolyl isomerase Pin1 in neuronal signaling in epilepsy

Cited by 5 publications

References 166 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

Pin1-Catalyzed Conformation Changes Regulate Protein Ubiquitination and Degradation

Rett and Rett-related disorders: Common mechanisms for shared symptoms?

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