ERK MAPK signaling pathway inhibition as a potential target to prevent autophagy alterations in Spinal Muscular Atrophy motoneurons
Abstract Spinal Muscular Atrophy (SMA) is a severe genetic neuromuscular disorder that occurs in childhood and is caused by misexpression of the survival motor neuron (SMN) protein. SMN reduction induces spinal cord motoneuron (MN) degeneration, which leads to progressive muscular atrophy and weakne...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01409-x |
| _version_ | 1797850168604753920 |
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| author | Alba Sansa Maria P. Miralles Maria Beltran Ferran Celma-Nos Jordi Calderó Ana Garcera Rosa M. Soler |
| author_facet | Alba Sansa Maria P. Miralles Maria Beltran Ferran Celma-Nos Jordi Calderó Ana Garcera Rosa M. Soler |
| author_sort | Alba Sansa |
| collection | DOAJ |
| description | Abstract Spinal Muscular Atrophy (SMA) is a severe genetic neuromuscular disorder that occurs in childhood and is caused by misexpression of the survival motor neuron (SMN) protein. SMN reduction induces spinal cord motoneuron (MN) degeneration, which leads to progressive muscular atrophy and weakness. The link between SMN deficiency and the molecular mechanisms altered in SMA cells remains unclear. Autophagy, deregulation of intracellular survival pathways and ERK hyperphosphorylation may contribute to SMN-reduced MNs collapse, offering a useful strategy to develop new therapies to prevent neurodegeneration in SMA. Using SMA MN in vitro models, the effect of pharmacological inhibition of PI3K/Akt and ERK MAPK pathways on SMN and autophagy markers modulation was studied by western blot analysis and RT-qPCR. Experiments involved primary cultures of mouse SMA spinal cord MNs and differentiated SMA human MNs derived from induced pluripotent stem cells (iPSCs). Inhibition of the PI3K/Akt and the ERK MAPK pathways reduced SMN protein and mRNA levels. Importantly, mTOR phosphorylation, p62, and LC3-II autophagy markers protein level were decreased after ERK MAPK pharmacological inhibition. Furthermore, the intracellular calcium chelator BAPTA prevented ERK hyperphosphorylation in SMA cells. Our results propose a link between intracellular calcium, signaling pathways, and autophagy in SMA MNs, suggesting that ERK hyperphosphorylation may contribute to autophagy deregulation in SMN-reduced MNs. |
| first_indexed | 2024-04-09T18:57:09Z |
| format | Article |
| id | doaj.art-7f17bffa2fa34d3ba5d982e79730d9e4 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-09T18:57:09Z |
| publishDate | 2023-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-7f17bffa2fa34d3ba5d982e79730d9e42023-04-09T11:08:08ZengNature Publishing GroupCell Death Discovery2058-77162023-04-019111110.1038/s41420-023-01409-xERK MAPK signaling pathway inhibition as a potential target to prevent autophagy alterations in Spinal Muscular Atrophy motoneuronsAlba Sansa0Maria P. Miralles1Maria Beltran2Ferran Celma-Nos3Jordi Calderó4Ana Garcera5Rosa M. Soler6Neuronal Signaling Unit, Experimental Medicine Department, Universitat de Lleida-IRBLleidaNeuronal Signaling Unit, Experimental Medicine Department, Universitat de Lleida-IRBLleidaNeuronal Signaling Unit, Experimental Medicine Department, Universitat de Lleida-IRBLleidaNeuronal Signaling Unit, Experimental Medicine Department, Universitat de Lleida-IRBLleidaPatologia Neuromuscular Experimental, Experimental Medicine Department, Universitat de Lleida-IRBLleidaNeuronal Signaling Unit, Experimental Medicine Department, Universitat de Lleida-IRBLleidaNeuronal Signaling Unit, Experimental Medicine Department, Universitat de Lleida-IRBLleidaAbstract Spinal Muscular Atrophy (SMA) is a severe genetic neuromuscular disorder that occurs in childhood and is caused by misexpression of the survival motor neuron (SMN) protein. SMN reduction induces spinal cord motoneuron (MN) degeneration, which leads to progressive muscular atrophy and weakness. The link between SMN deficiency and the molecular mechanisms altered in SMA cells remains unclear. Autophagy, deregulation of intracellular survival pathways and ERK hyperphosphorylation may contribute to SMN-reduced MNs collapse, offering a useful strategy to develop new therapies to prevent neurodegeneration in SMA. Using SMA MN in vitro models, the effect of pharmacological inhibition of PI3K/Akt and ERK MAPK pathways on SMN and autophagy markers modulation was studied by western blot analysis and RT-qPCR. Experiments involved primary cultures of mouse SMA spinal cord MNs and differentiated SMA human MNs derived from induced pluripotent stem cells (iPSCs). Inhibition of the PI3K/Akt and the ERK MAPK pathways reduced SMN protein and mRNA levels. Importantly, mTOR phosphorylation, p62, and LC3-II autophagy markers protein level were decreased after ERK MAPK pharmacological inhibition. Furthermore, the intracellular calcium chelator BAPTA prevented ERK hyperphosphorylation in SMA cells. Our results propose a link between intracellular calcium, signaling pathways, and autophagy in SMA MNs, suggesting that ERK hyperphosphorylation may contribute to autophagy deregulation in SMN-reduced MNs.https://doi.org/10.1038/s41420-023-01409-x |
| spellingShingle | Alba Sansa Maria P. Miralles Maria Beltran Ferran Celma-Nos Jordi Calderó Ana Garcera Rosa M. Soler ERK MAPK signaling pathway inhibition as a potential target to prevent autophagy alterations in Spinal Muscular Atrophy motoneurons Cell Death Discovery |
| title | ERK MAPK signaling pathway inhibition as a potential target to prevent autophagy alterations in Spinal Muscular Atrophy motoneurons |
| title_full | ERK MAPK signaling pathway inhibition as a potential target to prevent autophagy alterations in Spinal Muscular Atrophy motoneurons |
| title_fullStr | ERK MAPK signaling pathway inhibition as a potential target to prevent autophagy alterations in Spinal Muscular Atrophy motoneurons |
| title_full_unstemmed | ERK MAPK signaling pathway inhibition as a potential target to prevent autophagy alterations in Spinal Muscular Atrophy motoneurons |
| title_short | ERK MAPK signaling pathway inhibition as a potential target to prevent autophagy alterations in Spinal Muscular Atrophy motoneurons |
| title_sort | erk mapk signaling pathway inhibition as a potential target to prevent autophagy alterations in spinal muscular atrophy motoneurons |
| url | https://doi.org/10.1038/s41420-023-01409-x |
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