Bryostatin-1 boosts cell survival in lab model of ALS
Therapy activates PKC-epsilon, which is reduced in the motor cortex
Bryostatin-1, a molecule being developed to treat amyotrophic lateral sclerosis (ALS), improved cell survival in a lab model of the disease, a new study reports.
The therapy is known to activate PKC-epsilon, a protein that’s significantly reduced in ALS patients’ motor cortex, a brain region involved in muscle movement that’s damaged in the disease. By activating PKC-epsilon, bryostatin-1 was able to protect nerve cells from damage and death. The protein is important for regulating the health of nerve cells.
The study, “The [epsilon]-Isozyme of Protein Kinase C (PKC[epsilon]) 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,” was published in the International Journal of Molecular Sciences.
Bryostatin-1 was first found in certain marine animals. Synaptogenix is developing bryostatin-1 for several other neurological conditions along with ALS.
PKC-epsilon’s role in ALS
In this study, an independent team of scientists in Italy evaluated the potential role of PKC-epsilon in ALS. They looked first at gene expression data from dozens of people with or without the disease and found ALS patients overall didn’t show clear changes in the activation for the gene used to make PKC-epsilon.
In a subset of ALS patients defined previously based on their gene expression activity — called the SALS2 group — the PKC-epsilon (PRKCE) gene was significantly decreased compared with people without the disease.
A reduced activity of the gene was also seen in another dataset in which patients were divided into three groups based on their molecular characteristics. Those with a strong activation of nerve-supporting glial cells and inflammation had significantly lower activation of this gene than controls, but those whose mechanisms were marked by reactivation of retrotransposons (jumping genes) or with evidence of specific cellular stress mechanisms had normal PRKCE gene activation.
“We observed that [PKC-epsilon gene] expression level does not show differences when ALS is considered as a single entity, while it displays a significant downregulation in particular molecular subtypes of sporadic ALS patients,” wrote the researchers, who then analyzed brain tissue from people in the SALS2 group and found reduced levels of PKC-epsilon protein, consistent with the gene expression results.
One of the gene changes that characterizes the SALS2 group is abnormal activation of the gene SOD1, which is mutated in up to 20% of familial ALS cases and up to 2% of sporadic cases.
The researchers examined PKC-epsilon in nerve cells derived from a common ALS mouse model that carries a mutation in the SOD1 gene and found PKC-epsilon protein levels were significantly reduced, but bryostatin-1 increased its levels and led to significant increases in cell survival.
“This study provides evidence that two key disease factors for ALS are deficits in the gene for the PKC[epsilon] enzyme and deficits in the amount of the activated PKC[epsilon] in neurons from the motor cortex of ALS patients. It is encouraging that Bryostatin-1 reversed these deficits in motor neuron models of the ALS cells,” Daniel Alkon, MD, president and chief scientific officer of Synaptogenix, said in a company press release.
“Our findings suggest that PKC[epsilon] alteration could play a role in ALS pathophysiology and that PKC[epsilon] agonism [activation] by Bryostatin-1 may represent a potential neuroprotective strategy against motor neuronal degeneration — at least in a specific subgroup of sporadic ALS patients,” Sebastiano Cavallaro, MD, PhD, study co-author at the National Research Council in Italy, said.
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