Integrated analysis of endoplasmic reticulum stress regulators’ expression identifies distinct subtypes of autism spectrum disorder

Li, Yanjun; Gao, Songyin; Meng, Yuelan

doi:10.3389/fpsyt.2023.1136154

Cited by 3 publications

References 69 publications

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Is cholesterol both the lock and key to abnormal transmembrane signals in Autism Spectrum Disorder?

Lingwood

2024

Lipids Health Dis

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Disturbances in cholesterol homeostasis have been associated with ASD. Lipid rafts are central in many transmembrane signaling pathways (including mTOR) and changes in raft cholesterol content affect their order function. Cholesterol levels are controlled by several mechanisms, including endoplasmic reticulum associated degradation (ERAD) of the rate limiting HMGCoA reductase. A new approach to increase cholesterol via temporary ERAD blockade using a benign bacterial toxin-derived competitor for the ERAD translocon is suggested.A new lock and key model for cholesterol/lipid raft dependent signaling is proposed in which the rafts provide both the afferent and efferent ‘tumblers’ across the membrane to allow ‘lock and key’ receptor transmembrane signals.

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Is cholesterol both the lock and key to abnormal transmembrane signals in Autism Spectrum Disorder?

Lingwood

2024

Lipids Health Dis

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Causal association between mTOR-dependent circulating protein levels and autism spectrum disorder: a Mendelian randomization study

Fu,

Dong,

Chen

et al. 2024

Preprint

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Background Overactivation of the mTOR signaling pathway is a critical mechanism in the pathogenesis of autism spectrum disorder (ASD). However, the causal relationships between key molecules downstream of the mTOR signaling pathway and ASD remains unclear. This study aimed to explore the causal associations between seven mTOR-dependent circulating protein levels and ASD. Methods Instrumental variables (IVs) used as proxies for mTOR-dependent circulating protein levels were derived from the proteomics-GWAS INTERVAL study (3,301 participants) and a serum protein GWAS study in an Icelandic population (5,368 participants). Two ASD summary datasets were obtained from a meta-analysis study of ASD GWAS datasets (22,196 cases and 32,504 controls) and the FinnGen Consortium (646 cases and 301,879 controls), respectively. We applied two-sample Mendelian randomization (MR) to assess whether there is a causal association between seven mTOR-dependent circulating protein levels and ASD. Furthermore, validation analyses of positive exposures in the discovery cohort were performed to confirm the reliability of the findings. Results In this two-sample MR study, plasma PKCα level was found to be causally related to ASD in both the discovery cohort (IVW: OR = 1.15, 95% CI = 1.05–1.25, p = 0.002) and the validation cohort (IVW: OR = 1.14, 95% CI = 1.02–1.27, p = 0.017). Conclusions There was a causal association between the plasma level of PKCα and ASD, suggesting PKCα as a potential biomarker for the prevention, monitoring and treatment of ASD. However, whether PKCα can play a role in the clinical management of ASD remains to be demonstrated in future research.

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The ER Stress Induced in Human Neuroblastoma Cells Can Be Reverted by Lumacaftor, a CFTR Corrector

Pecoraro,

Serra,

Pascale

et al. 2024

CIMB

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Most neurodegenerative diseases share a common etiopathogenesis, the accumulation of protein aggregates. An imbalance in homeostasis brought on by the buildup of misfolded proteins within the endoplasmic reticulum (ER) results in ER stress in the cell. Three distinct proteins found in the ER membrane—IRE1α, PERK, and ATF6—control the unfolded protein response (UPR), a signal transduction pathway that is triggered to restore normal physiological conditions. Buildup of misfolded proteins in ER lumen leads to a shunting of GRP78/BiP, thus triggering the UPR. PERK autophosphorylation leads to activation of ATF4, the transcription factor; finally, ATF6 activates the UPR’s target genes, including GRP78/Bip. Accordingly, the UPR is a cellular reaction to an ER stress state that, if left unchecked for an extended period, results in apoptosis and irreversible damage. The identification of caspase 4, which is in the ER and is selectively activated by apoptotic stimuli caused by reticular stress, further demonstrated the connection between reticular stress and programed cell death. Moreover, oxidative stress and ER stress are linked. Oxidative stress is brought on by elevated quantities of radical oxygen species, both mitochondrial and cytosolic, that are not under the enzymatic regulation of superoxide dismutases, whose levels fall with increasing stress. Here, we evaluated the activity of Vx-809 (Lumacaftor), a drug used in cystic fibrosis, in SH-SY5Y neuronal cells, in which an ER stress condition was induced by Thapsigargin, to verify whether the drug could improve protein folding, suggesting its possible therapeutic use in proteinopathies, such as neurodegenerative diseases (NDs). Our data show that Vx-809 is involved in the significant reduction in protein produced under ER stress, particularly in the levels of Bip, ATF4, and ATF6 by Western blotting analysis, the reduction in ROS in the cytosol and mitochondria, and the reduction in the activation of the apoptotic pathway, measured by flow cytofluorimetry analysis and in restoring calcium homeostasis.

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Integrated analysis of endoplasmic reticulum stress regulators’ expression identifies distinct subtypes of autism spectrum disorder

Cited by 3 publications

References 69 publications

Is cholesterol both the lock and key to abnormal transmembrane signals in Autism Spectrum Disorder?

Is cholesterol both the lock and key to abnormal transmembrane signals in Autism Spectrum Disorder?

Causal association between mTOR-dependent circulating protein levels and autism spectrum disorder: a Mendelian randomization study

The ER Stress Induced in Human Neuroblastoma Cells Can Be Reverted by Lumacaftor, a CFTR Corrector

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