ABERRANT SIGNAL TRANSDUCTION AND MEMBRANE ABNORMALITIES IN AUTISM

Background: We have reported previously that the levels of aminoglycerophospholipids are altered in autism. There was a decrease in phosphatidylethanolamine (PE) and an increase in phosphatidylserine (PS) in the erythrocyte membrane of autistic subjects, resulting in decreased molar ratio of PE to PS.   We also reported increased membrane rigidity in autism.  These studies suggest that membrane lipid metabolism and cellular signaling associated with membrane functions may be altered in autism.

Objectives: To study membrane lipids in lymphoblast membrane from autism, and activities of enzymes involved in signal transduction such as phospholipids hydrolyzing enzyme (phospholipase A₂ -PLA₂), protein phosphorylating enzymes such as protein kinase C (PKC) and protein kinase A (PKA), and Ca²⁺/Mg²⁺-ATPase.

Methods: Phospholipid phosphorus was measured in lymphoblasts.  Ca²⁺/Mg²⁺-ATPase activity was measured in the erythrocyte membrane. Phospholipase A₂ activity was measured in the cytosol of lymphoblasts. PKC and PKA activities were measured in the lymphoblasts using protein kinase non-radioactive assay kits.

Results: PE to PS ratio was decreased in the lymphoblast membrane of autism.  PLA₂ activity was increased in the lymphoblasts of autism as compared with controls, suggesting that arachiodonic acid-mediated signal pathways may be altered in autism.  We also studied the activities of membrane-associated enzymes that control the cellular signaling.  The activity of Ca²⁺ / Mg ²⁺-ATPase was higher in erythrocyte membrane of autism as compared to controls, suggesting that intracellular calcium levels may be altered in autism. We then measured the Ca²⁺-dependent PKC activity in the lymphoblasts from autism and control subjects.  PKC activity was decreased in both cytosolic and membrane fractions in autism as compared to controls.  On the other hand, the activity of cAMP-dependent PKA was increased in autistic lymphoblasts as compared to control lymphoblasts.

Conclusions: Autism is associated with membrane phospholipids abnormalities, and alterations in the membrane-associated enzyme activities involved in cellular signaling pathways.