The #949;-Isozyme of Protein Kinase C 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

• Published in: International journal of molecular sciences 2023-08, Vol.24 (16)
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Cell death; Cellular signal transduction; Development and progression; Isoenzymes; Medical research; Medicine, Experimental; Nervous system diseases; Neurons; Photographic industry; Protein kinases; RNA; Scientific equipment and supplies industry
• ISSN: 1422-0067
• DOI: 10.3390/ijms241612825

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.