Small molecule cognitive enhancer reverses age-related memory decline in mice

Krukowski, Karen; Nolan, Amber; Frias, Elma S.; Boone, Morgane; Ureta, Gonzalo; Grue, Katherine; Paladini, Maria Serena; Elizarraras, Edward; Delgado, Luz; Bernales, Sebastián; Walter, Peter; Rosi, Susanna

doi:10.7554/elife.62048

Cited by 114 publications

(74 citation statements)

References 76 publications

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“…In an AD cellular model, ISRIB attenuated Aβ-induced neuronal cell death without affecting Aβ production [143]. Interestingly, ISRIB enhances memory, possibly by restoring protein synthesis, also improving working memory in old mice [208]. Long-term potentiation and cognition were restored and dendritic spines recovered by treatment with ISRIB or GSK2656157 of mice subjected to TBI [135,144].…”

Section: Perk Pathway Inhibitionmentioning

confidence: 99%

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

2021

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With the extension of life span in recent decades, there is an increasing burden of late-onset neurodegenerative diseases, for which effective treatments are lacking. Neurodegenerative diseases include the widespread Alzheimer’s disease (AD) and Parkinson’s disease (PD), the less frequent Huntington’s disease (HD) and Amyotrophic Lateral Sclerosis (ALS) and also rare early-onset diseases linked to mutations that cause protein aggregation or loss of function in genes that maintain protein homeostasis. The difficulties in applying gene therapy approaches to tackle these diseases is drawing increasing attention to strategies that aim to inhibit cellular toxicity and restore homeostasis by intervening in cellular pathways. These include the unfolded protein response (UPR), activated in response to endoplasmic reticulum (ER) stress, a cellular affliction that is shared by these diseases. Special focus is turned to the PKR-like ER kinase (PERK) pathway of the UPR as a target for intervention. However, the complexity of the pathway and its ability to promote cell survival or death, depending on ER stress resolution, has led to some confusion in conflicting studies. Both inhibition and activation of the PERK pathway have been reported to be beneficial in disease models, although there are also some reports where they are counterproductive. Although with the current knowledge a definitive answer cannot be given on whether it is better to activate or to inhibit the pathway, the most encouraging strategies appear to rely on boosting some steps without compromising downstream recovery.

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Section: Perk Pathway Inhibitionmentioning

confidence: 99%

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

2021

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“…ISRIB molecule, discovered in 2013, in contrast to PERK inhibitors, acts below eIF2 and directly reverses attenuation of the eIF2B by phosphorylated eIF2 33,46,47 . ISRIB has been proposed as a promising drug in the brain malignant conditions and age-related memory decline 48,49 , as well as in some metastatic tumours 50,51,52,53…”

Section: Discussionmentioning

confidence: 99%

Targeting Integrated Stress Response by ISRIB combined with imatinib attenuates STAT5 signaling and eradicates therapy-resistant Chronic Myeloid Leukemia cells

Dudka

Hoser

Mondal

et al. 2021

Preprint

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Integrated Stress Response (ISR) facilitates cellular adaptation to variable environmental conditions by reprogramming cellular response. Activation of ISR was reported in neurological disorders and solid tumours, but its function in hematological malignancies remains largely unknown. Previously we showed that ISR is activated in chronic myeloid leukemia (CML) CD34+ cells, and its activity correlates with disease progression and imatinib resistance. Here we demonstrate that inhibition of ISR by small molecule ISRIB, but not by PERK inhibitor GSK2656157, restores sensitivity to imatinib and eliminates CM Blast Crisis (BC) D34+ resistant cells. We found that in Patient Derived Xenograft (PDX) mouse model bearing CD34+ imatinib/dasatinib-resistant CML blasts with PTPN11 gain-of-function mutation, combination of imatinib and ISRIB decreases leukemia engraftment. Furthermore, genes related to SGK3, RAS/RAF/MAPK, JAK2 and IFNγ pathways were downregulated upon combined treatment. Remarkably, we confirmed that ISRIB and imatinib combination decreases STAT5 phosphorylation and inhibits expression of STAT5-target genes responsible for proliferation, viability and stress response. Thus, our data point to a substantial effect of imatinib and ISRIB combination, that results in transcriptomic deregulation and eradication of imatinib-resistant cells. Our findings suggest such drug combination might improve therapeutic outcome of TKI-resistant leukemia patients exhibiting constitutive STAT5 activation.

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“…The property of SFSV NSs, which directly binds to eIF2B and prevents the attenuation of cap-dependent translation, is somewhat similar to that of ISRIB, a small molecule that acts as an allosteric eIF2(αP) antagonist, binding eIF2B to disfavor its interaction with eIF2(αP) (Schoof et al, 2021; Zyryanova et al, 2021). Interestingly, ISRIB has shown promising effects in various animal models of neuropathological conditions, such as traumatic brain injury (Chou et al, 2017), amyotrophic lateral sclerosis (ALS) (Bugallo et al, 2020), Down syndrome (Zhu et al, 2019), and prion disease (Halliday et al, 2015), and even in the normal aging process (Krukowski et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

eIF2B-capturing viral protein NSs suppresses the integrated stress response

Kashiwagi

Shichino

Osaki

et al. 2021

Preprint

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Various stressors such as viral infection lead to the suppression of cap-dependent translation and the activation of the integrated stress response (ISR), since the stress-induced phosphorylated eukaryotic translation initiation factor 2 [eIF2(αP)] tightly binds to eIF2B to prevent it from exchanging guanine nucleotides on unphosphorylated eIF2. Sandfly fever Sicilian virus (SFSV) evades this cap-dependent translation suppression through the interaction between its nonstructural protein NSs and host eIF2B. Our cryo-electron microscopy (cryo-EM) analysis revealed that SFSV NSs binds to the α-subunit of eIF2B in a competitive manner with eIF2(αP). Together with SFSV NSs, eIF2B exhibits normal nucleotide exchange activity even in the presence of eIF2(αP). A genome-wide ribosome profiling analysis clarified that SFSV NSs in human cultured cells attenuates the ISR. Furthermore, SFSV NSs exhibited neuroprotective effects against the ISR-inducing stress. Since the ISR inhibition is beneficial in various neurological disease models, SFSV NSs is promising as a therapeutic ISR inhibitor.

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Small molecule cognitive enhancer reverses age-related memory decline in mice

Cited by 114 publications

References 76 publications

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

Targeting Integrated Stress Response by ISRIB combined with imatinib attenuates STAT5 signaling and eradicates therapy-resistant Chronic Myeloid Leukemia cells

eIF2B-capturing viral protein NSs suppresses the integrated stress response

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