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J Cell Physiol. 2019 Apr;234(4):5203-5214. doi: 10.1002/jcp.27328. Epub 2018 Sep 21.

Molecular mechanisms involved in the protective effect of pituitary adenylate cyclase-activating polypeptide in an in vitro model of amyotrophic lateral sclerosis.

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Department of Biomedical and Biotechnological Sciences, Section of Human Anatomy and Histology, University of Catania, Catania, Italy.
Department of Human Science and Promotion of Quality of Life, San Raffaele Open University of Rome, Rome, Italy.
Department of Biological, Geological and Environmental Sciences, Section of Animal Biology, University of Catania, Catania, Italy.
Institute of Neurological Sciences, National Research Council, Catania, Italy.


Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Based on transcriptional profiles of motor cortex samples, in a previous work, we were able to classify two subgroups of sporadic ALS (SALS) patients, named SALS1 and SALS2. A further meta-analysis study has revealed sixteen drug targets commonly deregulated in SALS2 and superoxide dismutase 1 (SOD1) G93A mice. The identified candidate drug targets included pituitary adenylate cyclase-activating polypeptide (PACAP), epidermal growth factor receptor (EGFR) and matrix metallopeptidase-2 (MMP-2). By using a motor neuron-like hybrid cell line (NSC-34) expressing human SOD1 G93A as an in vitro model of ALS, here we investigated the functional correlation among these three genes. Our results have shown that PACAP increases cell viability following serum deprivation. This effect is induced through EGFR transactivation mediated by protein kinase A stimulation. Furthermore, EGFR phosphorylation activates mitogen-activated protein kinases/extracellular signal-regulated kinases 1 and 2 survival signaling pathway and increases MMP-2 expression, significantly reduced by serum starvation. These results suggest that a deeper characterization of mechanisms involved in PACAP/EGFR/MMP-2 axis activation in G93A SOD1 mutated neurons may allow identifying new targets for ALS therapy.


amyotrophic lateral sclerosis (ALS); epidermal growth factor receptor (EGFR); extracellular signal-regulated kinases 1 and 2 (ERK1/2); matrix metallopeptidase-2 (MMP-2); pituitary adenylate cyclase-activating polypeptide (PACAP)


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