Prakash Chudalayandi

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Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke

iScience (2021)

Julia Cappelli Pamela Khacho Boyang Wang Alexandra Sokolovski Wafae Bakkar

Ischemic stroke is the second leading cause of death worldwide. Following an ischemic event, neuronal death is triggered by uncontrolled glutamate release leading to overactivation of glutamate sensitive N-methyl-d-aspartate receptor (NMDAR). For gating, NMDARs require not only the binding of glutamate, but also of glycine or a glycine-like compound as a co-agonist. Low glycine doses enhance NMDAR function, whereas high doses trigger glycine-induced NMDAR internalization (GINI) in vitro. Here, we report that following an ischemic event, in vivo, GINI also occurs and provides neuroprotection in the presence of a GlyT1 antagonist (GlyT1-A). Mice pretreated with a GlyT1-A, which increases synaptic glycine levels, exhibited smaller stroke volume, reduced cell death, and minimized behavioral deficits following stroke induction by either photothrombosis or endothelin-1. Moreover, we show evidence that in ischemic conditions, GlyT1-As preserve the vasculature in the peri-infarct area. Therefore, GlyT1 could be a new target for the treatment of ischemic stroke.

Stroke

Nimodipine

Internalization

10.1016/j.isci.2021.103539

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Citations (14)

Glycine transporter-1 antagonist provides 1 neuroprotection in vivo

Research Square (Research Square) (2021)

Richard Bergeron Julia Cappelli Pamela Khacho Boyang Wang Alexandra Sokolovski

Abstract Glycine fulfills several roles in biology including protein synthesis, inhibitory transmission via glycine receptor activation and excitatory transmission through glutamate-sensitive N-methyl-D-aspartate receptors (NMDARs). Low glycine doses enhance NMDAR function while high doses trigger glycine-induced NMDAR internalization (GINI) in vitro. The physiological relevance of GINI has been questioned given that the high-affinity glycine transporter type 1 (GlyT1), located on astrocytes and neurons, maintains synaptic glycine concentrations far below the level that would saturate the glycine binding site (GBS) on NMDARs. Here, we report evidence that GINI occurs also in vivo and is neuroprotective following ischemic insult. Mice pre-treated with a GlyT1 antagonist (GlyT1-A), which increased glycine levels, exhibited smaller stroke volume, reduced cell death, and minimized behavioural deficits following stroke induction by either photothrombosis or endothelin-1. We demonstrate that in a modified in vitro ischemic paradigm, glycine is released at levels surpassing what occurs during ischemia alone. Therefore, glycine accumulates in the synaptic cleft, enhances occupancy of GBS and reaches the set point to trigger GINI. We report that GINI is observed during stroke, in vivo, only in the presence of a GlyT1-A. Moreover, we show evidence of a protective effect on the vasculature in the peri-infarct area. Therefore, these data strongly suggest that GlyT1 is a therapeutic target to prevent cell death following an ischemic event.

10.21203/rs.3.rs-460311/v1

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The spindle position checkpoint is coordinated by the Elm1 kinase

The Journal of Cell Biology (2010)

Jeffrey K. Moore Prakash Chudalayandi Richard A. Heil‐Chapdelaine John A. Cooper

How dividing cells monitor the effective transmission of genomes during mitosis is poorly understood. Budding yeast use a signaling pathway known as the spindle position checkpoint (SPC) to ensure the arrival of one end of the mitotic spindle in the nascent daughter cell. An important question is how SPC activity is coordinated with mother–daughter polarity. We sought to identify factors at the bud neck, the junction between mother and bud, which contribute to checkpoint signaling. In this paper, we show that the protein kinase Elm1 is an obligate regulator of the SPC, and this function requires localization of Elm1 to the bud neck. Furthermore, we show that Elm1 promotes the activity of the checkpoint kinase Kin4. These findings reveal a novel function for Elm1 in the SPC and suggest how checkpoint activity may be linked to cellular organization.

Spindle checkpoint

Polarity (international relations)

10.1083/jcb.201006092

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Citations (36)

Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

Molecular Pharmacology (2016)

Adrian Y. C. Wong Elitza Hristova Nina Ahlskog Louis-Alexandre Tassé Johnny K. Ngsee

The sigma-1 receptor (σ-1R) is an endoplasmic reticulum resident chaperone protein involved in a plethora of cellular functions, and whose disruption has been implicated in a wide range of diseases. Genetic analysis has revealed two σ-1R mutants involved in neuromuscular disorders. A point mutation (E102Q) in the ligand-binding domain results in the juvenile form of amyotrophic lateral sclerosis (ALS16), and a 20 amino-acid deletion (Δ31–50) in the putative cytosolic domain leads to a form of distal hereditary motor neuropathy. We investigated the localization and functional properties of these mutants in cell lines using confocal imaging and electrophysiology. The σ-1R mutants exhibited a significant increase in mobility, aberrant localization, and enhanced block of the inwardly rectifying K⁺ channel K_ir2.1, compared with the wild-type σ-1R. Thus, these σ-1R mutants have different functional properties that could contribute to their disease phenotypes.

Sigma-1 Receptor

Chaperone (clinical)

10.1124/mol.116.104018

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Citations (28)

Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke

Research Square (Research Square) (2021)

Richard Bergeron Julia Cappelli Pamela Khacho Boyang Wang Alexandra Sokolovski

Abstract Ischemic stroke is the second leading cause of death worldwide. Compelling evidence demonstrates that following an ischemic event, neuronal death is triggered by uncontrolled glutamate release leading to overactivation of glutamate sensitive N-methyl-D-aspartate receptor (NMDAR). For gating, NMDARs require not only the binding of glutamate, but also the binding of glycine or a glycine-like compound as a co-agonist. Glycine fulfills several roles in biology including protein synthesis, inhibitory transmission via glycine receptor activation and excitatory transmission through NMDARs. Low glycine doses enhance NMDAR function while high doses trigger glycine-induced NMDAR internalization (GINI) in vitro. The physiological relevance of GINI has been questioned given that the high-affinity glycine transporter type 1 (GlyT1), located on astrocytes and neurons, maintains synaptic glycine concentrations far below the level that would saturate the glycine binding site (GBS). Here, we report that following an ischemic event, in vivo, GINI also occurs and provides neuroprotection. Mice pre-treated with a GlyT1 antagonist (GlyT1-A), which increases glycine synaptic levels, exhibited smaller stroke volume, reduced cell death, and minimized behavioural deficits following stroke induction by either photothrombosis or endothelin-1. Therefore, increasing glycine levels in the synaptic cleft will enhance GBS occupancy and will reach the set point to trigger GINI. However, we report that GINI is triggered during ischemic stroke, in vivo, only in the presence of GlyT1-As. Moreover, we show evidence that in ischemic conditions, GlyT1-As preserve the vasculature in the peri-infarct area. Therefore, the clinical efficacy of GlyT1-As should be tested for the treatment of ischemic stroke.

10.21203/rs.3.rs-460311/v2

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Self-excision of the antibiotic resistance gene nptII using a heat inducible Cre-loxP system from transgenic potato

Plant Molecular Biology (2006)

Wilmer J. Cuéllar Amélie C. M. Gaudin Dennis Solórzano Armando Casas Luis Ñopo

Selectable marker

Cre recombinase

Kanamycin

Marker gene

Transposase

Cre-Lox recombination

10.1007/s11103-006-9004-3

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Citations (100)

The Role of Sigma‐1‐Receptor in Endoreticulum Stress and Alzheimer's Disease.

Alzheimer s & Dementia (2022)

Thinh Nguyen Kayla Flemming Prakash Chudalayandi Richard Bergeron

Abstract Background One evident hallmark of Alzheimer's Disease (AD) is the irregular accumulation of proteins such as Aβ and pTau. This accumulation could alleviate ER stress and trigger an integrated signaling cascade called the unfolded protein response (UPR). UPR reduces the number of misfolded proteins and further inhibits abnormal protein accumulation. Targeting ER stress may therefore be an effective treatment for AD. One protein of interest that plays a role in modulating ER stress is the Sigma‐1 receptor (Sig1R). Sig1R agonists have been shown to be neuroprotective and anti‐amnesic in AD mouse models. However, the mechanism of action remains largely unknown. Method In our study, we use primary MEF cells derived from Wild‐type and Knock‐out Sig1R mouse models to examine the role of Sig1R in ER stress. We treated cells with an acute ER stressor, DTT, and measured transcript levels of target genes under the UPR branches. Furthermore, we used Chromosomal Immunoprecipitation (ChIP) to identify regulators of SIG1R gene during stress. Result We observed that the loss of Sig1R compromised the PERK pathway. KO MEFs had a slow recovery from stress suggesting Sig1R plays a role in re‐establishing homeostasis following stress. Following DTT treatment, mRNA and protein levels of Sig1R increase significantly over the course of recovery. ChIP uncovered three CHOP, a major player in the UPR, binding sites within the promoter of SIG1R, and each site had a distinct temporal binding pattern over the course of cell recovery. This increase in binding correlates with an increase in Sig1R expression. This showed that Sig1R is a chaperone downstream of CHOP, and that the up‐regulation of Sig1R might be crucial in re‐establishing homeostasis. Finally, our imaging data showed an increase in localization of Sig1R with extracellular vesicles. We further hypothesized that the high expression of Sig‐1R may have a role in the removal of misfolded proteins, perhaps Aβ. Therefore, we have ongoing experiments looking at the effect of Aβ on our models. Conclusion Our study has the potential to unravel the implications of Sig1R in AD by showing that it is transcriptionally and translationally regulated in response to stress induced by misfolded proteins.

Sigma-1 Receptor

10.1002/alz.065584

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