ArticleAutophagy2021
Modulation of the IGF1R-MTOR pathway attenuates motor neuron toxicity of human ALS SOD1
Article in Autophagy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 41 citations in OpenAlex.
- Gene expression profiles in sporadic ALS fibroblasts define disease subtypes and the metabolic effects of the investigational drug EH301.Human molecular genetics · 2022Pooled it
- Neurodegenerative diseases and immune system: From pathogenic mechanism to therapy.Neural regeneration research · 2026Article
- Cell-intrinsic mTOR/LET-363 influences morphological aging of the ALM touch receptor neuron in Caenorhabditis elegans.PloS one · 2026Article
- Non-cell autonomous autophagy in amyotrophic lateral sclerosis: A new promising target?Neurobiology of disease · 2026Review
- Article
- Activity and Heterogeneity of Astrocytes in Neurological Diseases: Molecular Mechanisms and Therapeutic Targets.MedComm · 2025Review
- The Redox Revolution in Brain Medicine: Targeting Oxidative Stress with AI, Multi-Omics and Mitochondrial Therapies for the Precision Eradication of Neurodegeneration.International journal of molecular sciences · 2025Review
- S-9-PAHSA Protects Against High-Fat Diet-Induced Diabetes-Associated Cognitive Impairment via Gut Microbiota Regulation.CNS neuroscience & therapeutics · 2025Article
- Gene therapy breakthroughs in ALS: a beacon of hope for 20% of ALS patients.Translational neurodegeneration · 2025Review
- The Role of mTOR in Amyotrophic Lateral Sclerosis.Biomedicines · 2025Review
- Significance of Programmed Cell Death Pathways in Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- High salt diet induces cognitive impairment and is linked to the activation of IGF1R/mTOR/p70S6K signaling.Metabolic brain disease · 2024Article
- Molecular hallmarks of ageing in amyotrophic lateral sclerosis.Cellular and molecular life sciences : CMLS · 2024Review
- The Diverse Roles of Reactive Astrocytes in the Pathogenesis of Amyotrophic Lateral Sclerosis.Brain sciences · 2024Review
- Article
- The role of glial autophagy in Alzheimer's disease.Molecular psychiatry · 2023Review
- Ibrutinib Delays ALS Installation and Increases Survival of SOD1Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2023Article
- Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger CaActa pharmaceutica Sinica. B · 2023Article
- AMPKα1 Deficiency in Astrocytes from a Rat Model of ALS Is Associated with an Altered Metabolic Resilience.Biomolecules · 2023Article
- Advances in the mTOR signaling pathway and its inhibitor rapamycin in epilepsy.Brain and behavior · 2023Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
ALS (amyotrophic lateral sclerosis), the most common motor neuron disease, causes muscle denervation and rapidly fatal paralysis. While motor neurons are the most affected cells in ALS, studies on the pathophysiology of the disease have highlighted the importance of non-cell autonomous mechanisms, which implicate astrocytes and other glial cells. In ALS, subsets of reactive astrocytes lose their physiological functions and become toxic for motor neurons, thereby contributing to disease pathogenesis. Evidence of astrocyte contribution to disease pathogenesis are well established in cellular and animal models of familial ALS linked to mutant SOD1, where astrocytes promote motor neuron cell death. The mechanism underlying astrocytes reactivity in conditions of CNS injury have been shown to involve the MTOR pathway. However, the role of this conserved metabolic signaling pathway, and the potential therapeutic effects of its modulation, have not been investigated in ALS astrocytes. Here, we show elevated activation of the MTOR pathway in human-derived astrocytes harboring mutant SOD1, which results in inhibition of macroautophagy/autophagy, increased cell proliferation, and enhanced astrocyte reactivity. We demonstrate that MTOR pathway activation in mutant SOD1 astrocytes is due to post-transcriptional upregulation of the IGF1R (insulin like growth factor 1 receptor), an upstream positive modulator of the MTOR pathway. Importantly, inhibition of the IGF1R-MTOR pathway decreases cell proliferation and reactivity of mutant SOD1 astrocytes, and attenuates their toxicity to motor neurons. These results suggest that modulation of astrocytic IGF1R-MTOR pathway could be a viable therapeutic strategy in SOD1 ALS and potentially other neurological diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.