Neuroprotective Efficacy of a Sigma 2 Receptor/TMEM97 Modulator (DKR-1677) after Traumatic Brain Injury

Vázquez‐Rosa, Edwin; Watson, Michael R.; Sahn, James J.; Hodges, Timothy R.; Schroeder, Rachel; Cintrón-Pérez, Coral J.; Shin, Meong Cheol; Yin, Terry; Emery, Josie; Martin, Stephen F.; Liebl, Daniel J.; Pieper, Andrew A.

doi:10.1021/acschemneuro.8b00543

Cited by 55 publications

(48 citation statements)

References 33 publications

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“…Previous studies in cancer cells showed that a number of Sigma 2 receptor ligands induce apoptosis and cytotoxicity by generating reactive oxygen species [8,26]. On the other hand, Sigma 2 receptor antagonists are shown to provide a protective effect following traumatic brain injury [27]. Our study extended these findings and showed that TMEM97 played a protective role in RPE against oxidative stresses, providing a potential drug target to alleviate RPE degeneration in AMD.…”

Section: To Enablesupporting

confidence: 77%

Functional study of the AMD-associated geneTMEM97in retinal pigmented epithelium using CRISPR interference

Wang

Urrutia-Cabrera

Mora

et al. 2020

Preprint

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Age-related macular degeneration (AMD) is a blinding disease characterised by dysfunction of the retinal pigmented epithelium (RPE) which culminates in disruption or loss of the neurosensory retina. Genome-wide association studies have identified >65 genetic risk factors for AMD, including the TMEM97 locus. TMEM97 encodes the Sigma-2 receptor which is involved in apoptosis and cytotoxicity across a range of neurodegenerative diseases. However, the expression pattern of TMEM97 in the human retina and its functional role in retinal cells has remained elusive. Here we utilised CRISPR interference (CRISPRi) to investigate the functional role of TMEM97 in the retina. Transcriptome analysis of all major cell types within the human retina showed that TMEM97 is expressed in the RPE, retinal ganglion cells (RGCs) and amacrine cells. Using CRISPRi, we performed loss-of-function study of TMEM97 in the human RPE cell line, ARPE19. We generated a stable ARPE19 cell line expressing dCas9-KRAB which facilitated knockdown of TMEM97 using specific sgRNAs. Our results show that knockdown of TMEM97 in ARPE19 exerts a protective effect against oxidative stress-induced cell death. This work provides the first functional study of TMEM97 in RPE and supports the role of TMEM97 in AMD pathobiology. Our study highlights the potential for using CRISPRi to study AMD genetics, and the CRISPRi cell line generated here provided an useful in vitro tool for functional studies of other AMD-associated genes.

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Section: To Enablesupporting

confidence: 77%

Functional study of the AMD-associated geneTMEM97in retinal pigmented epithelium using CRISPR interference

Wang

Urrutia-Cabrera

Mora

et al. 2020

Preprint

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“…Notably, σ2R is involved in several disease states, and the utility of its exogenous ligands as cancer therapeutics and diagnostic tools has been reported [15][16][17]. Additionally, σ2R has been implicated in multiple neurodegenerative and neurological disorders [18,19]. Similar to the ligands of σ1R, certain molecules that bind to σ2R also reduce mechanical hypersensitivity in a spared nerve injury model [20].…”

Section: Introductionmentioning

confidence: 99%

The Sigma 2 receptor promotes and the Sigma 1 receptor inhibits mu-opioid receptor-mediated antinociception

et al. 2020

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The Sigma-1 receptor (σ1R) has emerged as an interesting pharmacological target because it inhibits analgesia mediated by mu-opioid receptors (MOR), and also facilitates the development of neuropathic pain. Based on these findings, the recent cloning of the Sigma-2 receptor (σ2R) led us to investigate its potential role as a regulator of opioid analgesia and of pain hypersensitivity in σ2R knockout mice. In contrast to σ1R deficient mice, σ2R knockout mice developed mechanical allodynia following establishment of chronic constriction injury-induced neuropathic pain, which was alleviated by the σ1R antagonist S1RA. The analgesic effects of morphine, [D-Ala, N-MePhe, Gly-ol]-encephalin (DAMGO) and β-endorphin increased in σ1R−/− mice and diminished in σ2R−/− mice. The analgesic effect of morphine was increased in σ2R−/− mice by treatment with S1RA. However, σ2R−/− mice and wild-type mice exhibited comparable antinociceptive responses to the delta receptor agonist [D-Pen2,5]-encephalin (DPDPE), the cannabinoid type 1 receptor agonist WIN55,212-2 and the α2-adrenergic receptor agonist clonidine. Therefore, while σR1 inhibits and σ2R facilitates MOR-mediated analgesia these receptors exchange their roles when regulating neuropathic pain perception. Our study may help identify new pharmacological targets for diminishing pain perception and improving opioid detoxification therapies.

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“…Further investigation may shed new lights on BRD2-dominated transcription programs that sensitively respond to cholesterol level changes. Along this line, studies on BETs and S2R, both targets of increasing clinical (trial) drugs 6,13,24,36,37 , may synergize interventional opportunities for cholesterol-associated pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

BRD2 regulation of sigma-2 receptor expression upon cytosolic cholesterol deprivation

Shen

Xie

et al. 2019

Preprint

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Traditionally a pharmacologic target for antipsychotic treatment, the sigma-2 receptor (S2R) was recently implicated in cholesterol homeostasis. Here we investigated the transcriptional regulation of S2R by the Bromo/ExtraTerminal epigenetic reader family (BETs, including BRD2, 3, 4) upon cholesterol perturbation.Cytosolic cholesterol deprivation was induced using an export blocker of lysosomal cholesterol in ARPE19 cells. This condition upregulated mRNA and protein levels of S2R, and of SREBP2 but not SREBP1, transcription factors key to cholesterol/fatty acid metabolism. Silencing BRD2 but not BRD4 (though widely deemed as a master regulator) or BRD3 prevented S2R upregulation induced by cholesterol deprivation. Silencing SREBP2 but not SREBP1 diminished S2R expression. Furthermore, BRD2 co-immunoprecipitated with the SREBP2 transcriptionactive N-terminal domain, and chromatin immunoprecipitation-qPCR showed a BRD2 occupancy at the S2R gene promoter.In summary, this study reveals a novel BRD2/SREBP2 cooperative regulation of S2R transcription in response to cytosolic cholesterol deprivation, thus shedding new light on epigenetic control of cholesterol biology.

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Neuroprotective Efficacy of a Sigma 2 Receptor/TMEM97 Modulator (DKR-1677) after Traumatic Brain Injury

Cited by 55 publications

References 33 publications

Functional study of the AMD-associated geneTMEM97in retinal pigmented epithelium using CRISPR interference

Functional study of the AMD-associated geneTMEM97in retinal pigmented epithelium using CRISPR interference

The Sigma 2 receptor promotes and the Sigma 1 receptor inhibits mu-opioid receptor-mediated antinociception

BRD2 regulation of sigma-2 receptor expression upon cytosolic cholesterol deprivation

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