Stress exposure affects amyotrophic lateral sclerosis pathogenesis via PI3K/Akt and focal adhesion pathways: evidence from three experimental models
Abstract Amyotrophic lateral sclerosis (ALS) is a multifactorial motor neuron (MN) disease, characterized by several cellular dysfunctions, many of which are shared by different neurodegenerative diseases. Here, we investigated whether a stressful lifestyle might exacerbate the altered mechanisms an...
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Nature Portfolio
2025-05-01
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| author | Daniela Maria Rasà Ilaria Stoppa Noémie Bérenger-Currias Elena Pasho Sorana Ciura Edor Kabashi Cécile Martinat Marina Boido |
| author_facet | Daniela Maria Rasà Ilaria Stoppa Noémie Bérenger-Currias Elena Pasho Sorana Ciura Edor Kabashi Cécile Martinat Marina Boido |
| author_sort | Daniela Maria Rasà |
| collection | DOAJ |
| description | Abstract Amyotrophic lateral sclerosis (ALS) is a multifactorial motor neuron (MN) disease, characterized by several cellular dysfunctions, many of which are shared by different neurodegenerative diseases. Here, we investigated whether a stressful lifestyle might exacerbate the altered mechanisms and affect the disease progression in ALS-predisposed conditions. To model stress in vivo, SOD1 G93A mice underwent a chronic unpredicted mild stress protocol. This resulted in a significant impairment in body weight gain and motor performance, in a gender-specific manner. Moreover, the gene expression of Col1a1, Col1a2 and Il6 was strongly dysregulated in motor cortex and/or spinal cord of stressed mice. To assess the direct impact of stress on MNs, NSC-34 hSOD1 G93A cells underwent oxygen and glucose deprivation. Compared to NSC-34 hSOD1 WT, mutated MNs exhibited a reduced capacity to cope with stress. By performing gene expression, protein-protein interaction, gene ontology and pathway enrichment analyses, we also revealed the pivotal role of the PI3K/Akt and focal adhesion pathways (triggered by Gsk3b, Il6, Igf1 and/or collagen) in mediating stress response. Similar results were observed in stressed human iPSCs-derived TARDBP G298S MNs. In conclusion, our results suggest that the PI3K/Akt and focal adhesion pathways play a crucial role in stress response across different ALS-predisposed models: the study paves the way for novel therapeutic targets and highlights the relevance of a healthy lifestyle. |
| format | Article |
| id | doaj-art-b233d1edb6b34ba69f1cb70fe736586e |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-b233d1edb6b34ba69f1cb70fe736586e2025-08-20T03:08:25ZengNature PortfolioScientific Reports2045-23222025-05-0115111610.1038/s41598-025-02167-9Stress exposure affects amyotrophic lateral sclerosis pathogenesis via PI3K/Akt and focal adhesion pathways: evidence from three experimental modelsDaniela Maria Rasà0Ilaria Stoppa1Noémie Bérenger-Currias2Elena Pasho3Sorana Ciura4Edor Kabashi5Cécile Martinat6Marina Boido7Department of Neuroscience “Rita Levi Montalcini”, Neuroscience Institute Cavalieri Ottolenghi, University of TurinDepartment of Neuroscience “Rita Levi Montalcini”, Neuroscience Institute Cavalieri Ottolenghi, University of TurinUniversité Paris-Saclay, Université d’Evry, Inserm, I-Stem, UMR861Laboratory of Translational Research for Neurological Disorders, Imagine Institute, INSERM UMR 1163, 75015, Université Paris CitéLaboratory of Translational Research for Neurological Disorders, Imagine Institute, INSERM UMR 1163, 75015, Université Paris CitéLaboratory of Translational Research for Neurological Disorders, Imagine Institute, INSERM UMR 1163, 75015, Université Paris CitéUniversité Paris-Saclay, Université d’Evry, Inserm, I-Stem, UMR861Department of Neuroscience “Rita Levi Montalcini”, Neuroscience Institute Cavalieri Ottolenghi, University of TurinAbstract Amyotrophic lateral sclerosis (ALS) is a multifactorial motor neuron (MN) disease, characterized by several cellular dysfunctions, many of which are shared by different neurodegenerative diseases. Here, we investigated whether a stressful lifestyle might exacerbate the altered mechanisms and affect the disease progression in ALS-predisposed conditions. To model stress in vivo, SOD1 G93A mice underwent a chronic unpredicted mild stress protocol. This resulted in a significant impairment in body weight gain and motor performance, in a gender-specific manner. Moreover, the gene expression of Col1a1, Col1a2 and Il6 was strongly dysregulated in motor cortex and/or spinal cord of stressed mice. To assess the direct impact of stress on MNs, NSC-34 hSOD1 G93A cells underwent oxygen and glucose deprivation. Compared to NSC-34 hSOD1 WT, mutated MNs exhibited a reduced capacity to cope with stress. By performing gene expression, protein-protein interaction, gene ontology and pathway enrichment analyses, we also revealed the pivotal role of the PI3K/Akt and focal adhesion pathways (triggered by Gsk3b, Il6, Igf1 and/or collagen) in mediating stress response. Similar results were observed in stressed human iPSCs-derived TARDBP G298S MNs. In conclusion, our results suggest that the PI3K/Akt and focal adhesion pathways play a crucial role in stress response across different ALS-predisposed models: the study paves the way for novel therapeutic targets and highlights the relevance of a healthy lifestyle.https://doi.org/10.1038/s41598-025-02167-9Bioinformatic analysisExposomeMolecular mechanismsNeuromuscular diseaseStressor |
| spellingShingle | Daniela Maria Rasà Ilaria Stoppa Noémie Bérenger-Currias Elena Pasho Sorana Ciura Edor Kabashi Cécile Martinat Marina Boido Stress exposure affects amyotrophic lateral sclerosis pathogenesis via PI3K/Akt and focal adhesion pathways: evidence from three experimental models Scientific Reports Bioinformatic analysis Exposome Molecular mechanisms Neuromuscular disease Stressor |
| title | Stress exposure affects amyotrophic lateral sclerosis pathogenesis via PI3K/Akt and focal adhesion pathways: evidence from three experimental models |
| title_full | Stress exposure affects amyotrophic lateral sclerosis pathogenesis via PI3K/Akt and focal adhesion pathways: evidence from three experimental models |
| title_fullStr | Stress exposure affects amyotrophic lateral sclerosis pathogenesis via PI3K/Akt and focal adhesion pathways: evidence from three experimental models |
| title_full_unstemmed | Stress exposure affects amyotrophic lateral sclerosis pathogenesis via PI3K/Akt and focal adhesion pathways: evidence from three experimental models |
| title_short | Stress exposure affects amyotrophic lateral sclerosis pathogenesis via PI3K/Akt and focal adhesion pathways: evidence from three experimental models |
| title_sort | stress exposure affects amyotrophic lateral sclerosis pathogenesis via pi3k akt and focal adhesion pathways evidence from three experimental models |
| topic | Bioinformatic analysis Exposome Molecular mechanisms Neuromuscular disease Stressor |
| url | https://doi.org/10.1038/s41598-025-02167-9 |
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