Possible role of microgliopathy in the pathogenesis of Nasu–Hakola disease

Abstract

Nasu–Hakola disease (NHD) is a rare autosomal recessive disorder characterized by progressive dementia and multifocal bone cysts, caused by genetic mutations of either DAP 12 or TREM 2. TREM 2 acts as a phagocytic receptor expressed on osteoclasts, dendritic cells, macrophages and microglia, where it constitutes a signaling complex with an adaptor molecule DAP 12, leading to phosphorylation and activation of the downstream kinase, spleen tyrosine kinase (Syk). Previous studies hypothesized that a loss‐of‐function of microglial TREM 2/DAP 12 plays a central role in the pathogenesis of NHD. However, by immunohistochemistry, we recently found that TREM 2 is not detectable on microglia, but expressed on small populations of intravascular monocytes/macrophages and neurons in both control brains and DAP 12‐mutated NHD brains despite massive accumulation of Iba1‐immunoreactive microglia. Furthermore, we found that both neurons and microglia express Y525/Y526‐phosphorylated Syk (pS yk), and the expression levels of neuronal pS yk are elevated substantially in NHD brains compared with control brains. These observations suggest that TREM 2 expression on microglia in vivo is a transient event, depending on their microenvironment, and presently undefined non‐TREM 2/DAP 12 signaling pathways positively regulate activation of Syk in NHD brains. Thus, we have not yet obtained definite immunohistochemical evidence for supporting an active role of microglia in NHD brains. Here, we discuss a possible role of microgliopathy in the pathogenesis of NHD.