UPR activation specifically modulates glutamate neurotransmission in the cerebellum of a mouse model of autism

Trobiani, Laura; Favaloro, Flores Lietta; Castro, Maria Amalia Di; Mattia, Michela Di; Cariello, Marica; Miranda, Elena; Canterini, Sonia; Stefano, Maria Egle De; Comoletti, Davide; Limatola, Cristina; Jaco, Antonella De

doi:10.1016/j.nbd.2018.08.026

Cited by 25 publications

(39 citation statements)

References 68 publications

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“…Indeed, various abnormalities in immunological markers or immune functions, including CSF or brain tissue-associated immune abnormalities have been a recurring theme in ASD research (Abraham et al, 2019). In addition, as mentioned above, ER stress has been observed in the brains of autistic children (Crider et al, 2017), and UPR activation has also been observed in the cerebellum of a mouse model of autism (Trobiani et al, 2018). Therefore, these proteins still have the potential to become diagnostic markers.…”

Section: Discussionmentioning

confidence: 87%

“…Interestingly, a recent study showed a significant increase in the mRNA levels of ATF4, ATF6, PERK, XBP1, CHOP, and IRE1 in the middle frontal gyrus of ASD subjects (Crider et al, 2017). Another study showed that the activation of UPR specifically regulated glutamate neurotransmission in the cerebellum of a mouse model of autism (Trobiani et al, 2018). Taken together, these results support that ER stress and UPR may be involved in pathogenesis of ASD.…”

Section: Discussionmentioning

confidence: 99%

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Proteomics Study of Peripheral Blood Mononuclear Cells (PBMCs) in Autistic Children

Shen

Feng

Zhang

et al. 2019

Front. Cell. Neurosci.

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Autism is one of the most common neurological developmental disorder associated with social isolation and restricted interests in children. The etiology of this disorder is still unknown. There is neither any confirmed laboratory test nor any effective therapeutic strategy to diagnose or cure it. To search for biomarkers for early detection and exploration of the disease mechanisms, here, we investigated the protein expression signatures of peripheral blood mononuclear cells (PBMCs) in autistic children compared with healthy controls by using isobaric tags for relative and absolute quantitation (iTRAQ) proteomics approach. The results showed a total of 41 proteins as differentially expressed in autistic group as compared to control. These proteins are found associated with metabolic pathways, endoplasmic reticulum (ER) stress and protein folding, endocytosis, immune and inflammatory response, plasma lipoprotein particle organization, and cell adhesion. Among these, 17 proteins (13 up-regulated and four down-regulated) are found to be linked with mitochondria. Eight proteins including three already reported proteins in our previous studies were selected to be verified. Five already reported autism associated pro-inflammatory cytokines [interferon-γ (IFN-γ), interleukin-1β (IL-1β), IL-6, IL-12, and tumor necrosis factor-α (TNF-α)] were detected in plasma by enzyme-linked immunosorbent assay (ELISA) analysis. The results were consistent with proteomic results and reports from previous literature. These results proposed that PBMCs from autistic children might be activated, and ER stress, unfolded protein response (UPR), acute-phase response (APR), inflammatory response, and endocytosis may be involved in autism occurrence. These reported proteins may serve as potential biomarkers for early diagnosis of autism. More specifically, simultaneous detection of three proteins [complement C3 (C3), calreticulin (CALR), and SERPINA1] in the plasma and PBMCs could increase the authenticity of detection.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Proteomics Study of Peripheral Blood Mononuclear Cells (PBMCs) in Autistic Children

Shen

Feng

Zhang

et al. 2019

Front. Cell. Neurosci.

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“…Retention of R451C NLGN3 in the ER activates all three branches of the Unfolded Protein Response (UPR): inositol‐requiring enzyme‐1α (IRE1α), protein kinase R (PKR)‐like endoplasmic reticulum kinase (PERK), and activating transcription factor 6α (ATF6α) . The activation of this cellular response, along with loss of NLGN3 localization and accumulation of mutated proteins, all probably contributes to the autistic‐like behavior observed in the Knock‐In mice expressing R451C NLGN3 …”

Section: Introductionmentioning

confidence: 99%

A Lipophilic 4‐Phenylbutyric Acid Derivative That Prevents Aggregation and Retention of Misfolded Proteins

Azoulay-Ginsburg

Trobiani

Setini

et al. 2020

Chemistry A European J

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Chemical chaperonesp reventprotein aggregation. However,t he use of chemicalc haperones as drugs against diseases due to protein aggregation is limitedb yt he very high active concentrations (mm range) required to mediate their effect. One of the most commonc hemical chaperones is 4-phenylbutyric acid (4-PBA). Despite itsu nfavorablep harmacokinetic properties, 4-PBA was approved as ad rug to treat ornithine cycled iseases.H ere, we report that 2-isopropyl-4-phenylbutanoic acid (5)h as been found to be 2-10fold more effective than 4-PBA in several in vitro modelso f protein aggregation.I mportantly,c ompound 5 reduced the secretion rate of autism-linked Arg451Cys Neuroligin3 (R451CN LGN3).[a] S. Azoulay-Ginsburg,L .L evy,P rof. A. Gruzman

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“…Activation of PERK by autophosphorylation leads to phosphorylation of eukaryotic initiation factor 2 α (eIF2α), reducing the synthesis of critical synaptic proteins in neurons that affects memory processes and synaptic plasticity associated with intellectual disability, cognition, and addiction (Trinh et al, 2014 ; Placzek et al, 2016 ). PERK/eIF2α has also been linked to the pathophysiology of autism spectrum disorder (ASD) and mutant Neuroligin3 induced UPR and to anxiety-like behavior and GABAergic neuron damage in the amygdala (Ulbrich et al, 2016 ; Trobiani et al, 2018 ). IRE1α upon activation dimerizes and auto-phosphorylates which activates its kinase and RNase domain.…”

Section: The Unfolded Protein Responsementioning

confidence: 99%

“…In neuronal PC12 cells, expressing the autism-linked mutant R451C neuroligin3 PERK and other UPR signals were activated (Ulbrich et al, 2016 ). In a mouse knock-in model for this mutant neuroligin3, UPR was activated specifically in the cerebellum with an increased excitatory current in Purkinje cells, that was restored to normal levels upon PERK inhibition (Trobiani et al, 2018 ). More studies are required to understand how the mutant neuroligin3 induced UPR activation is related to ASD associated synaptic pathologies.…”

Section: Perk 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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UPR activation specifically modulates glutamate neurotransmission in the cerebellum of a mouse model of autism

Cited by 25 publications

References 68 publications

Proteomics Study of Peripheral Blood Mononuclear Cells (PBMCs) in Autistic Children

Proteomics Study of Peripheral Blood Mononuclear Cells (PBMCs) in Autistic Children

A Lipophilic 4‐Phenylbutyric Acid Derivative That Prevents Aggregation and Retention of Misfolded Proteins

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

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