Abstract
BackgroundNasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by sclerosing leukoencephalopathy and multifocal bone cysts, caused by a loss-of-function mutation of either DAP12 or TREM2. TREM2 and DAP12 constitute a receptor/adaptor signaling complex expressed exclusively on osteoclasts, dendritic cells, macrophages, and microglia. Neuropathologically, NHD exhibits profound loss of myelin and accumulation of axonal spheroids, accompanied by intense gliosis accentuated in the white matter of the frontal and temporal lobes. At present, the molecular mechanism responsible for development of leukoencephalopathy in NHD brains remains totally unknown.MethodsBy immunohistochemistry, we studied the expression of microtubule-associated protein 1 light chain 3 (LC3), an autophagosome marker, in 5 NHD and 12 control brains.ResultsIn all NHD brains, Nogo-A-positive, CNPase-positive oligodendrocytes surviving in the non-demyelinated white matter intensely expressed LC3. They also expressed ubiquitin, ubiquilin-1, and histone deacetylase 6 (HDAC6) but did not express Beclin 1 or sequestosome 1 (p62). Substantial numbers of axonal spheroids were also labeled with LC3 in NHD brains. In contrast, none of oligodendrocytes expressed LC3 in control brains. Furthermore, surviving oligodendrocytes located at the demyelinated lesion edge of multiple sclerosis (MS) did not express LC3, whereas infiltrating Iba1-positive macrophages and microglia intensely expressed LC3 in MS lesions.ConclusionsThese results propose a novel hypothesis that aberrant regulation of autophagy might induce oligodendrogliopathy causative of leukoencephalopathy in NHD brains.
Highlights
Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by sclerosing leukoencephalopathy and multifocal bone cysts, caused by a loss-of-function mutation of either DNAX-activation protein 12 (DAP12) or triggering receptor expressed on myeloid cells 2 (TREM2)
Oligodendrocytes surviving in the non-demyelinated white matter of NHD brains intensely expressed light chain 3 (LC3) immunoreactivity First, we validated the specificity of anti-LC3 antibody PM036 by western blot analysis of total protein extracted from mouse oligodendrocyte-type 2 astrocyte (O2A) progenitor cells termed OS3 [30], following a 48-hour exposure to rapamycin, a potent inducer of autophagy
Double labeling verified that LC3-expressing cells accumulated in the non-demyelinated white matter of NHD brains coexpressed 2’,3’-cyclic nucleotide 3′ phosphodiesterase (CNPase), a cell type-specific marker of oligodendrocytes (Figure 2f)
Summary
Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by sclerosing leukoencephalopathy and multifocal bone cysts, caused by a loss-of-function mutation of either DAP12 or TREM2. TREM2 and DAP12 constitute a receptor/adaptor signaling complex expressed exclusively on osteoclasts, dendritic cells, macrophages, and microglia. Nasu-Hakola disease (NHD), designated polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; OMIM 221770), is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts [1,2]. TREM2 in a pattern of autosomal recessive inheritance could differentiate NHD from hereditary diffuse leukoencephalopathy with spheroids (HDLS; OMIM 221820), a rare autosomal dominant disorder presenting with clinicopathological similarities to NHD, which is caused by genetic mutations in the colony-stimulating factor 1 receptor (CSF1R) gene [8]. Syk transduces a wide range of downstream signals involved in activation of phosphatidylinositol-3 kinase (PI3K), phospholipase C (PLC), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) [10]
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