Articolo in rivista, 2023, ENG, 10.3390/ijms241612825

The E-Isozyme of Protein Kinase C (PKCE) 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 V.; D'Amico A. G.; Maugeri G.; Morello G.; Guarnaccia M.; Magri B.; Aronica E.; Alkon D. L.; D'Agata V.; Cavallaro S.

CNR; Univ Catania; Univ Amsterdam; Synaptogenix Inc

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 ( alpha,beta, zeta and delta). Here, we detailed the distribution and cellular localization of the epsilon-isozyme of protein kinase C (PKC epsilon) in human postmortem motor cortex specimens and reported a significant decrease in both PKC epsilon mRNA (PRKCE) and protein immunoreactivity in a subset of sporadic ALS patients. We furthermore investigated the steady-state levels of both pan and phosphorylated PKC epsilon 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 phosphoPKC epsilon/panPKC epsilon ratio compared to the WT. Moreover, a brief pulse activation of PKC epsilon 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 PKC epsilon in ALS pathophysiology and suggests its pharmacological modulation as a potential neuroprotective strategy, at least in a subgroup of sporadic ALS patients.

International journal of molecular sciences (Print) 24 (16)

Keywords

PKC epsilon, PRKCE, amyotrophic lateral sclerosis, neurodegeneration, Bryostatin-1

CNR authors

Morello Giovanna Maria Alessandra, Cavallaro Sebastiano, Guarnaccia Maria, La Cognata Valentina

CNR institutes

IRIB – Istituto per la Ricerca e l'Innovazione Biomedica