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Open AccessArticle

PACAP Modulates the Autophagy Process in an In Vitro Model of Amyotrophic Lateral Sclerosis

Department of Human Science and Promotion of quality of Life, San Raffaele Open University of Rome, Via di Val Cannuta, 247, 00166 Roma, Italy
Section of Human Anatomy and Histology, Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia, 87, 95123 Catania, Italy
Section of Animal Biology, Department of Biological, Geological and Environmental Sciences, University of Catania, 95123 Catania, Italy
Institute for Biomedical Research and Innovation, Italian National Research Council, 95123 Catania, Italy
Department of Anatomy, MTA-PTE PACAP Research Group, University of Pecs Medical School, 7622 Pécs, Hungary
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(8), 2943;
Received: 17 February 2020 / Revised: 15 April 2020 / Accepted: 19 April 2020 / Published: 22 April 2020
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of complex etiology leading to motor neuron degeneration. Many gene alterations cause this pathology, including mutation in Cu, Zn superoxide dismutase (SOD1), which leads to its gain of function. Mutant SOD1 proteins are prone to aberrant misfolding and create aggregates that impair autophagy. The hypoxic stress is strictly linked to the disease progression since it induces uncontrolled autophagy activation and the consequent high rates of cell death. Previously, we showed that pituitary adenylate cyclase-activating polypeptide (PACAP) exerts neurotrophic activity in cultured mSOD1 motor neurons exposed to serum deprivation. To date, no studies have examined whether the protective effect of PACAP on mSOD1 cells exposed to hypoxic insult is mediated through the regulation of the autophagy process. In the present study, we used the neuroblastoma-spinal cord-34 (NSC-34) cell line, stably expressing human wild type or mutant SOD1 G93A, to represent a well characterized in vitro model of a familial form of ALS. These cells were exposed to 100-µM desferrioxamine mesylate salt for 24h, to mimic the hypoxic stress affecting motor neurons during the disease progression. Our results showed that PACAP treatment significantly reduced cell death and hypoxia-induced mSOD1 accumulation by modulating the autophagy process in G93A motor neurons, as revealed by the decreased LC3II and the increased p62 levels, two autophagy indicators. These results were also confirmed by evaluating the vacuole formation detected through light chain 3 (LC3) immunofluorescence. Furthermore, the PACAP effects on autophagy seem to be mediated through the activation of the MAPK/ERK signaling pathway. Overall, our data demonstrated that PACAP exerts an ameliorative effect on the mSOD1 motor neuron viability by modulating a hypoxia-induced autophagy process through activation of MAPK/ERK signaling cascade. View Full-Text
Keywords: PACAP; ALS; autophagy process; hypoxia condition PACAP; ALS; autophagy process; hypoxia condition
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MDPI and ACS Style

D’Amico, A.G.; Maugeri, G.; Saccone, S.; Federico, C.; Cavallaro, S.; Reglodi, D.; D’Agata, V. PACAP Modulates the Autophagy Process in an In Vitro Model of Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci. 2020, 21, 2943.

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