A ROLE FOR AMPLIFIED PROTEIN-KINASE-C ACTIVITY IN THE PATHOGENESIS OFAMYOTROPHIC-LATERAL-SCLEROSIS

Amyotrophic lateral sclerosis (ALS) is a human neurodegenerative disor der of unknown origin that is characterized by progressive degeneratio n of corticospinal tracts and anterior horn cells in the brainstem and spinal cord. Previous studies have indicated that motoneuron degenera tion associated with ALS may be triggered by mechanisms leading to inc reased intracellular Ca2+. In the present report, Ca2+-activated phosp holipid-dependent protein kinase C (PKC) was evaluated in cervical spi nal cords from ALS patients and control subjects. In patients who died with ALS, PKC histone H1 phosphotransferase activity was significantl y increased by 330% in cytosolic- and 118% in particulate-derived extr acts compared with controls. This increase in PKC phosphotransferase a ctivity appeared to be partially due to an increase in the amount of P KC protein present in ALS spinal cord tissue. PKC histone H1 phosphotr ansferase activities of cytosolic- and particulate-derived extracts fr om motor and visual cortex of ALS patients and controls were not stati stically different, nor were there differences in PKC histone H1 phosp hotransferase activity in platelets and leukocytes. The specific natur e of PKC alterations in affected regions of the CNS supports a role fo r PKC in the events leading to motoneuron death in sporadic ALS.