Pharmaceutical integrated stress response enhancement protects oligodendrocytes and provides a potential multiple sclerosis therapeutic

Way, Sharon W.; Podojil, Joseph R.; Clayton, Benjamin L.L.; Zaremba, Anita; Collins, Tassie L.; Kunjamma, Rejani B.; Robinson, Andrew P.; Brugarolas, Pedro; Miller, Robert H.; Miller, Stephen D.; Popko, Brian

doi:10.1038/ncomms7532

Cited by 94 publications

(109 citation statements)

References 57 publications

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“…One study found that, on average, ϳ2 M guanabenz can be detected in the brains of mice at 2 to 4 h postinjection (28), which corresponds to the concentration that we found to inhibit Toxoplasma proliferation in vitro (Fig. 1A).…”

Section: Discussionsupporting

confidence: 67%

Guanabenz Repurposed as an Antiparasitic with Activity against Acute and Latent Toxoplasmosis

Benmerzouga

Checkley

Ferdig

et al. 2015

Antimicrob Agents Chemother

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Toxoplasma gondii is a protozoan parasite that persists as a chronic infection. Toxoplasma evades immunity by forming tissue cysts, which reactivate to cause life-threatening disease during immune suppression. There is an urgent need to identify drugs capable of targeting these latent tissue cysts, which tend to form in the brain. We previously showed that translational control is critical during infections with both replicative and latent forms of Toxoplasma. Here we report that guanabenz, an FDA-approved drug that interferes with translational control, has antiparasitic activity against replicative stages of Toxoplasma and the related apicomplexan parasite Plasmodium falciparum (a malaria agent). We also found that inhibition of translational control interfered with tissue cyst biology in vitro. Toxoplasma bradyzoites present in these abnormal cysts were diminished and misconfigured, surrounded by empty space not seen in normal cysts. These findings prompted analysis of the efficacy of guanabenz in vivo by using established mouse models of acute and chronic toxoplasmosis. In addition to protecting mice from lethal doses of Toxoplasma, guanabenz has a remarkable ability to reduce the number of brain cysts in chronically infected mice. Our findings suggest that guanabenz can be repurposed into an effective antiparasitic with a unique ability to reduce tissue cysts in the brain.

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Section: Discussionsupporting

confidence: 67%

Guanabenz Repurposed as an Antiparasitic with Activity against Acute and Latent Toxoplasmosis

Benmerzouga

Checkley

Ferdig

et al. 2015

Antimicrob Agents Chemother

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“…Targeting the same pathway is also beneficial in a model of multiple sclerosis. Enhancement of PERK signaling by a genetic approach or sustained eIF2α phosphorylation with the GADD34 inhibitor guanabenz protects oligodendrocytes from death induced by EAE (Tsaytler et al, 2011; Lin et al, 2013; Way et al, 2015). Recently, Sephin1, a more specific GADD34 inhibitor, has been shown to largely prevent the motor, morphological, and molecular defects of S63del mice (Das et al, 2015).…”

Section: Erqc and Charcot-marie-tooth (Cmt) Neuropathiesmentioning

confidence: 99%

Endoplasmic Reticulum Protein Quality Control Failure in Myelin Disorders

Volpi¹,

Touvier²,

D’Antonio³

2017

Front. Mol. Neurosci.

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Reaching the correct three-dimensional structure is crucial for the proper function of a protein. The endoplasmic reticulum (ER) is the organelle where secreted and transmembrane proteins are synthesized and folded. To guarantee high fidelity of protein synthesis and maturation in the ER, cells have evolved ER-protein quality control (ERQC) systems, which assist protein folding and promptly degrade aberrant gene products. Only correctly folded proteins that pass ERQC checkpoints are allowed to exit the ER and reach their final destination. Misfolded glycoproteins are detected and targeted for degradation by the proteasome in a process known as endoplasmic reticulum-associated degradation (ERAD). The excess of unstructured proteins in the ER triggers an adaptive signal transduction pathway, called unfolded protein response (UPR), which in turn potentiates ERQC activities in order to reduce the levels of aberrant molecules. When the situation cannot be restored, the UPR drives cells to apoptosis. Myelin-forming cells of the central and peripheral nervous system (oligodendrocytes and Schwann cells) synthesize a large amount of myelin proteins and lipids and therefore are particularly susceptible to ERQC failure. Indeed, deficits in ERQC and activation of ER stress/UPR have been implicated in several myelin disorders, such as Pelizaeus-Merzbacher and Krabbe leucodystrophies, vanishing white matter disease and Charcot-Marie-Tooth neuropathies. Here we discuss recent evidence underlying the importance of proper ERQC functions in genetic disorders of myelinating glia.

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“…These target-dependent toxicities include pancreatic injury as well as behavioral inflexibility, which is a hallmark of autism spectrum disorders [74,75]. Inhibition of eIF2α phosphorylation may also exacerbate motor neuron disease [76,77]. …”

Section: Expert Opinionmentioning

confidence: 99%

The eIF2-alpha kinase HRI: a potential target beyond the red blood cell

Burwick

Aktas

2017

Expert Opinion on Therapeutic Targets

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Introduction The eIF2α kinase heme-regulated inhibitor (HRI) is one of four well-described kinases that phosphorylate eIF2α in response to various cell stressors, resulting in reduced ternary complex formation and attenuation of mRNA translation. Although HRI is well known for its role as a heme sensor in erythroid progenitors, pharmacologic activation of HRI has been demonstrated to have anti-cancer activity across a wide range of tumor sub-types. Here, the potential of HRI activators as novel cancer therapeutics is explored. Areas covered We provide an introduction to eIF2 signaling pathways in general, and specifically review data on the eIF2α kinase HRI in erythroid and non-erythroid cells. We review aspects of targeting eIF2 signaling in cancer and highlight promising data using HRI activators against tumor cells. Expert opinion Pharmacologic activation of HRI inhibits tumor growth as a single agent without appreciable toxicity in vivo. The ability of HRI activators to provide direct and sustained eIF2α phosphorylation without inducing oxidative stress or broad eIF2α kinase activation may be especially advantageous for tolerability. Combination therapy with established therapeutics may further augment anti-cancer activity to overcome disease resistance.

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Pharmaceutical integrated stress response enhancement protects oligodendrocytes and provides a potential multiple sclerosis therapeutic

Cited by 94 publications

References 57 publications

Guanabenz Repurposed as an Antiparasitic with Activity against Acute and Latent Toxoplasmosis

Guanabenz Repurposed as an Antiparasitic with Activity against Acute and Latent Toxoplasmosis

Endoplasmic Reticulum Protein Quality Control Failure in Myelin Disorders

The eIF2-alpha kinase HRI: a potential target beyond the red blood cell

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