Increased expression and activation of cytosolic phospholipase A₂ in the spinal cord of patients with sporadic amyotrophic lateral sclerosis

Compelling evidence identifies a link between cytotoxic effects of cytosolic phospholipase A₂ (cPLA₂) activity and neuron death in cell cultures. cPLA₂ catalyzes the hydrolysis of membrane phospholipids to produce and release arachidonate, leading to plasma membrane injury, inflammatory response and subsequent cell death. To assess a role for cPLA₂ in the pathomechanism of amyotrophic lateral sclerosis (ALS), we performed immunohistochemical, immunoblot, and densitometric analyses of cPLA₂ and its active form phosphorylated at S⁵⁰⁵ (p-cPLA₂) on spinal cords obtained at autopsy from ten sporadic ALS patients and ten age-matched controls. On sections, immunoreactivities for cPLA₂ and p-cPLA₂ were distinct and localized in almost all of the motor neurons, reactive astrocytes, and activated microglia in the ALS cases, while immunoreactivities were only weak or not at all observed in neurons and glia in the control cases. On immunoblots, both the cPLA₂/β-actin density ratio and the p-cPLA₂/cPLA₂ density ratio were significantly increased in the ALS group compared to the control group. There was no significant link between the densitometric data and the clinical phenotypes, age at death or disease duration of the ALS patients. These results provide in vivo evidence for increased expression and activation of cPLA₂ in motor neurons, reactive astrocytes, and activated microglia in ALS, suggesting occurrence of arachidonate cascade-induced motor neuron death via cell-autonomous and/or non-cell-autonomous mechanisms.