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<p>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, <i>SOD1</i><sup><i>G93A</i></sup> 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 <i>Col1a1</i>, <i>Col1a2</i> and <i>Il6</i> was strongly dysregulated in motor cortex and/or spinal cord of stressed mice. To assess the direct impact of stress on MNs, NSC-34 h<i>SOD1</i><sup>G93A</sup> cells underwent oxygen and glucose deprivation. Compared to NSC-34 h<i>SOD1</i><sup>WT</sup>, 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 <i>Gsk3b</i>, <i>Il6</i>, <i>Igf1</i> and/or collagen) in mediating stress response. Similar results were observed in stressed human iPSCs-derived <i>TARDBP</i><sup><i>G298S</i></sup> 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.</p>

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Stress exposure affects amyotrophic lateral sclerosis pathogenesis via PI3K/Akt and focal adhesion pathways: evidence from three experimental models

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月21日

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  • Daniela Maria Rasà,
  • Ilaria Stoppa,
  • Noémie Bérenger-Currias,
  • Elena Pasho,
  • Sorana Ciura,
  • Edor Kabashi,
  • Cécile Martinat,
  • Marina Boido

摘要

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, SOD1G93A 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 hSOD1G93A cells underwent oxygen and glucose deprivation. Compared to NSC-34 hSOD1WT, 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 TARDBPG298S 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.