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The ε-Isozyme of Protein Kinase C (PKCε) Is Impaired in ALS Motor Cortex and Its Pulse Activation by Bryostatin-1 Produces Long Term Survival in Degenerating SOD1-G93A Motor Neuron-like Cells

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease, characterized by a progressive depletion of upper and lower motor neurons (MNs) in the brain and spinal cord. The aberrant regulation of several PKC-mediated signal transduction pathways in A...

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Autores principales: La Cognata, Valentina, D’Amico, Agata Grazia, Maugeri, Grazia, Morello, Giovanna, Guarnaccia, Maria, Magrì, Benedetta, Aronica, Eleonora, Alkon, Daniel L., D’Agata, Velia, Cavallaro, Sebastiano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10454105/
https://www.ncbi.nlm.nih.gov/pubmed/37629005
http://dx.doi.org/10.3390/ijms241612825
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author La Cognata, Valentina
D’Amico, Agata Grazia
Maugeri, Grazia
Morello, Giovanna
Guarnaccia, Maria
Magrì, Benedetta
Aronica, Eleonora
Alkon, Daniel L.
D’Agata, Velia
Cavallaro, Sebastiano
author_facet La Cognata, Valentina
D’Amico, Agata Grazia
Maugeri, Grazia
Morello, Giovanna
Guarnaccia, Maria
Magrì, Benedetta
Aronica, Eleonora
Alkon, Daniel L.
D’Agata, Velia
Cavallaro, Sebastiano
author_sort La Cognata, Valentina
collection PubMed
description Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease, characterized by a progressive depletion of upper and lower motor neurons (MNs) in the brain and spinal cord. The aberrant regulation of several PKC-mediated signal transduction pathways in ALS has been characterized so far, describing either impaired expression or altered activity of single PKC isozymes (α, β, ζ and δ). Here, we detailed the distribution and cellular localization of the ε-isozyme of protein kinase C (PKCε) in human postmortem motor cortex specimens and reported a significant decrease in both PKCε mRNA (PRKCE) and protein immunoreactivity in a subset of sporadic ALS patients. We furthermore investigated the steady-state levels of both pan and phosphorylated PKCε in doxycycline-activated NSC-34 cell lines carrying the human wild-type (WT) or mutant G93A SOD1 and the biological long-term effect of its transient agonism by Bryostatin-1. The G93A-SOD1 cells showed a significant reduction of the phosphoPKCε/panPKCε ratio compared to the WT. Moreover, a brief pulse activation of PKCε by Bryostatin-1 produced long-term survival in activated G93A-SOD1 degenerating cells in two different cell death paradigms (serum starvation and chemokines-induced toxicity). Altogether, the data support the implication of PKCε in ALS pathophysiology and suggests its pharmacological modulation as a potential neuroprotective strategy, at least in a subgroup of sporadic ALS patients.
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spelling pubmed-104541052023-08-26 The ε-Isozyme of Protein Kinase C (PKCε) Is Impaired in ALS Motor Cortex and Its Pulse Activation by Bryostatin-1 Produces Long Term Survival in Degenerating SOD1-G93A Motor Neuron-like Cells La Cognata, Valentina D’Amico, Agata Grazia Maugeri, Grazia Morello, Giovanna Guarnaccia, Maria Magrì, Benedetta Aronica, Eleonora Alkon, Daniel L. D’Agata, Velia Cavallaro, Sebastiano Int J Mol Sci Article Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease, characterized by a progressive depletion of upper and lower motor neurons (MNs) in the brain and spinal cord. The aberrant regulation of several PKC-mediated signal transduction pathways in ALS has been characterized so far, describing either impaired expression or altered activity of single PKC isozymes (α, β, ζ and δ). Here, we detailed the distribution and cellular localization of the ε-isozyme of protein kinase C (PKCε) in human postmortem motor cortex specimens and reported a significant decrease in both PKCε mRNA (PRKCE) and protein immunoreactivity in a subset of sporadic ALS patients. We furthermore investigated the steady-state levels of both pan and phosphorylated PKCε in doxycycline-activated NSC-34 cell lines carrying the human wild-type (WT) or mutant G93A SOD1 and the biological long-term effect of its transient agonism by Bryostatin-1. The G93A-SOD1 cells showed a significant reduction of the phosphoPKCε/panPKCε ratio compared to the WT. Moreover, a brief pulse activation of PKCε by Bryostatin-1 produced long-term survival in activated G93A-SOD1 degenerating cells in two different cell death paradigms (serum starvation and chemokines-induced toxicity). Altogether, the data support the implication of PKCε in ALS pathophysiology and suggests its pharmacological modulation as a potential neuroprotective strategy, at least in a subgroup of sporadic ALS patients. MDPI 2023-08-15 /pmc/articles/PMC10454105/ /pubmed/37629005 http://dx.doi.org/10.3390/ijms241612825 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
La Cognata, Valentina
D’Amico, Agata Grazia
Maugeri, Grazia
Morello, Giovanna
Guarnaccia, Maria
Magrì, Benedetta
Aronica, Eleonora
Alkon, Daniel L.
D’Agata, Velia
Cavallaro, Sebastiano
The ε-Isozyme of Protein Kinase C (PKCε) Is Impaired in ALS Motor Cortex and Its Pulse Activation by Bryostatin-1 Produces Long Term Survival in Degenerating SOD1-G93A Motor Neuron-like Cells
title The ε-Isozyme of Protein Kinase C (PKCε) Is Impaired in ALS Motor Cortex and Its Pulse Activation by Bryostatin-1 Produces Long Term Survival in Degenerating SOD1-G93A Motor Neuron-like Cells
title_full The ε-Isozyme of Protein Kinase C (PKCε) Is Impaired in ALS Motor Cortex and Its Pulse Activation by Bryostatin-1 Produces Long Term Survival in Degenerating SOD1-G93A Motor Neuron-like Cells
title_fullStr The ε-Isozyme of Protein Kinase C (PKCε) Is Impaired in ALS Motor Cortex and Its Pulse Activation by Bryostatin-1 Produces Long Term Survival in Degenerating SOD1-G93A Motor Neuron-like Cells
title_full_unstemmed The ε-Isozyme of Protein Kinase C (PKCε) Is Impaired in ALS Motor Cortex and Its Pulse Activation by Bryostatin-1 Produces Long Term Survival in Degenerating SOD1-G93A Motor Neuron-like Cells
title_short The ε-Isozyme of Protein Kinase C (PKCε) Is Impaired in ALS Motor Cortex and Its Pulse Activation by Bryostatin-1 Produces Long Term Survival in Degenerating SOD1-G93A Motor Neuron-like Cells
title_sort ε-isozyme of protein kinase c (pkcε) is impaired in als motor cortex and its pulse activation by bryostatin-1 produces long term survival in degenerating sod1-g93a motor neuron-like cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10454105/
https://www.ncbi.nlm.nih.gov/pubmed/37629005
http://dx.doi.org/10.3390/ijms241612825
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