Phosphorylated Syk expression is enhanced in Nasu-Hakola disease brains.

Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by a loss-of-function mutation of DNAX-activation protein 12 (DAP12) or triggering receptor expressed on myeloid cells 2 (TREM2). TREM2 and DAP12 constitute a receptor/adaptor complex on myeloid cells. The post-receptor signals are transmitted via rapid phosphorylation of the immunoreceptor tyrosine-based activating motif (ITAM) of DAP12, mediated by Src protein tyrosine kinases, followed by binding of phosphorylated ITAM to Src homology 2 (SH2) domains of spleen tyrosine kinase (Syk), resulting in autophosphorylation of the activation loop of Syk. To elucidate the molecular mechanism underlying the pathogenesis of NHD, we investigated Syk expression and activation in the frontal cortex and the hippocampus of three NHD and eight control brains by immunohistochemistry. In NHD brains, the majority of neurons expressed intense immunoreactivities for Syk and Y525/Y526-phosphorylated Syk (pSyk) chiefly located in the cytoplasm, while more limited populations of neurons expressed Src. The levels of pSyk expression were elevated significantly in NHD brains compared with control brains. In both NHD and control brains, substantial populations of microglia and macrophages expressed pSyk, while the great majority of reactive astrocytes and myelinating oligodendrocytes did not express pSyk, Syk or Src. These observations indicate that neuronal expression of pSyk was greatly enhanced in the cerebral cortex and the hippocampus of NHD brains, possibly via non-TREM2/DAP12 signaling pathways involved in Syk activation.

On the activity of brain phospholipase A2 towards specifically labelled glycerophospholipids during subacute sclerosing panencephalitis.

1,2-Diacyl-sn-glycero-3-phosphorylcholine, -ethanolamine and -serine, specifically labelled with different fatty acids at either the 1- or 2-position, were prepared enzymatically using the acyltransferase system of rat liver microsomes. The substrates were subjected to hydrolysis by phospholipase A2 obtained from brain tissue of a normal and a case of subacute sclerosing panencephalitis (SSPE). In the pathological tissue and increase of approx. 50% in phospholipase A2 activity could be observed in comparison to that from the control brain for all investigated substrates. Experiments with phosphatidylethanolamines, specifically labelled with different fatty acids in the 2-position, revealed that the phospholipase A2 activity of the SSPE brain tissue was enhanced by about 50% when compared to the control brain regardless of the fatty acid constituent at the 2-position of the substrates.

On the effect of brain phospholipase A1 on specifically labelled glycerophospholipids in the course of subacute sclerosing panencephalitis.

The effect of phospholipase A1 of human brain on 1,2-diacyl-sn-glycero-3-phosphorylcholine, -ethanolamine and -serine, specifically labelled with different fatty acids at either the 1 or 2 position, was determined in subacute sclerosing panencephalitis. An increase of approximately 40% in the specific activity of phospholipase A1 could be observed for all substrates investigated during the demyelinating disorder. On investigating the specific activity of the enzyme with various molecular species of phosphatidylcholine and -ethanolamine, labelled at the 1 position with different radioactive fatty acids, we found that the phospholipase A1 preferentially removed those fatty acids from the 1 position of phosphatidylcholines that have the fewest double bonds, while oleic and linoleic acid were released at almost similar rates from phosphatidylethanolamine.