The Role and Therapeutic Potential of the Integrated Stress Response in Amyotrophic Lateral Sclerosis

Marlin, Elías; Viu-Idocin, Cristina; Arrasate, Montserrat; Aragón, Tomás

doi:10.3390/ijms23147823

Cited by 12 publications

(15 citation statements)

References 151 publications

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“…However, under chronic or excessive stress, ISR can also promote cell death. ISR is activated in ALS and can further promote the initiation of neurotoxicity after induction by stress ( Marlin et al, 2022 ). Thus, ISR may be a potential target for the treatment of ALS.…”

Section: Drugsmentioning

confidence: 99%

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New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022

2022

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily affects motor neurons in the brain and spinal cord. In the recent past, there have been just two drugs approved for treatment, riluzole and edaravone, which only prolong survival by a few months. However, there are many novel experimental drugs in development. In this review, we summarize 53 new drugs that have been evaluated in clinical trials from 2020 to 2022, which we have classified into eight mechanistic groups (anti-apoptotic, anti-inflammatory, anti-excitotoxicity, regulated integrated stress response, neurotrophic factors and neuroprotection, anti-aggregation, gene therapy and other). Six were tested in phase 1 studies, 31 were in phase 2 studies, three failed in phase 3 studies and stopped further development, and the remaining 13 drugs were being tested in phase 3 studies, including methylcobalamin, masitinib, MN-166, verdiperstat, memantine, AMX0035, trazodone, CNM-Au8, pridopidine, SLS-005, IONN363, tofersen, and reldesemtiv. Among them, five drugs, including methylcobalamin, masitinib, AMX0035, CNM-Au8, and tofersen, have shown potent therapeutic effects in clinical trials. Recently, AMX0035 has been the third medicine approved by the FDA for the treatment of ALS after riluzole and edaravone.

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Section: Drugsmentioning

confidence: 99%

“…and animal models. The heterogeneity in the ISR response in ALS patients may affect the success of clinical trials ( Marlin et al, 2022 ).…”

Section: Drugsmentioning

confidence: 99%

New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022

2022

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“…Based on this dual, fate‐defining capacity, independent studies have tried to elucidate the role and therapeutic potential of ISR exacerbation or inhibition in ALS (Marlin et al, 2022). Surprisingly, the emerging picture is not uniform: In some models, ISR enhancement is neuroprotective; however, ISR suppression can also mitigate the neurotoxicity of familial ALS neurotoxic alleles (Marlin et al, 2022). Besides, some of these studies remain controversial (Dzhashiashvili et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…ISR activation has been documented in sporadic ALS patients, induced pluripotent stem cell (iPSC)-derived MNs from sporadic and familial ALS patients and cellular and animal ALS models (Marlin et al, 2022). Studies performed in mutant SOD1 transgenic mice (a well-established familial ALS model; Bonifacino et al, 2021;Gurney et al, 1994) revealed two salient features of the ISR in this disease:…”

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confidence: 99%

Pharmacological inhibition of the integrated stress response accelerates disease progression in an amyotrophic lateral sclerosis mouse model

Marlin,

Valencia,

Peregrín

et al. 2023

British J Pharmacology

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Background and PurposeThe integrated stress response (ISR) regulates translation in response to diverse stresses. ISR activation has been documented in amyotrophic lateral sclerosis (ALS) patients and ALS experimental models. In experimental models, both ISR stimulation and inhibition prevented ALS neurodegeneration; however, what mode of ISR regulation would work in patients is still debated. We previously demonstrated that the ISR modulator ISRIB (an eIF2B activator) enhances survival of neurons expressing the ALS neurotoxic allele SOD1 G93A. Here, we tested the effect of two ISRIB‐like eIF2B activators (2BAct and PRXS571) in the disease progression of transgenic SOD1G93A mice.Experimental ApproachAfter a biochemical characterization in primary neurons, SOD1G93A mice were treated with 2BAct and PRXS571. Muscle denervation of vulnerable motor units was monitored with a longitudinal electromyographic test. We used a clinical score to document disease onset and progression; force loss was determined with hanging‐wire motor test. Motor neuronal survival was assessed by immunohistochemistry.Key ResultsIn primary neurons 2BAct and PRXS571 relieve the ISR‐imposed translational inhibition while maintaining high ATF4 levels. Electromyographic recordings evidenced an earlier and more dramatic muscle denervation in treated SOD1G93A mice that correlated with a decrease in motor neuron survival. Both compounds anticipated disease onset and shortened survival time.Conclusion and Implications2BAct and PRXS571 anticipate disease onset, aggravating muscle denervation and motor neuronal death of SOD1G93A mice. This study reveals that the ISR works as a neuroprotective pathway in ALS motor neurons and reveals the toxicity that eIF2B activators may display in ALS patients.

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“…When a return to homeostasis is not achieved, ISR signaling can activate apoptosis 3 . While acute activation of the ISR is adaptive, a chronic ISR signaling state is associated with a wide range of age-related and neurodegenerative pathologies, including Alzheimer's disease, brain injury-induced dementia, cancer, and Down syndrome [4][5][6][7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

A central helical fulcrum in eIF2B coordinates allosteric regulation of Integrated Stress Response signaling

Lawrence

Shoemaker

Deal

et al. 2022

Preprint

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The Integrated Stress Response (ISR) enables cells to survive a variety of acute stresses, but chronic activation of the ISR underlies age-related diseases. ISR signaling down-regulates translation and activates expression of stress-responsive factors that promote return to homeostasis, and is initiated by inhibition of the decameric guanine nucleotide exchange factor eIF2B. Conformational and assembly transitions regulate eIF2B activity, but the allosteric mechanisms controlling these dynamic transitions are unknown. Using hydrogen deuterium exchange-mass spectrometry and cryo-EM, we identified a single alpha-helix whose orientation allosterically controls eIF2B conformation and assembly. Biochemical and signaling assays show that this 'Switch-Helix' controls eIF2B activity and signaling in cells. In sum, the Switch-Helix acts as a fulcrum of eIF2B conformational regulation and is a highly conserved actuator of ISR signal transduction. This work uncovers a novel allosteric mechanism and unlocks new therapeutic possibilities for ISR-linked diseases.

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The Role and Therapeutic Potential of the Integrated Stress Response in Amyotrophic Lateral Sclerosis

Cited by 12 publications

References 151 publications

New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022

New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022

Pharmacological inhibition of the integrated stress response accelerates disease progression in an amyotrophic lateral sclerosis mouse model

A central helical fulcrum in eIF2B coordinates allosteric regulation of Integrated Stress Response signaling

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