title: Phosphorylated Syk expression is enhanced in Nasu-Hakola disease brains.
abstract: 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.
authors: Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University Department of Clinical Neuropathology, Tokyo, Japan. satoj@my-pharm.ac.jp
authors: Jun-Ichi
authors: J
authors: Satoh
authors: Hiroko
authors: H
authors: Tabunoki
authors: Tsuyoshi
authors: T
authors: Ishida
authors: Saburo
authors: S
authors: Yagishita
authors: Kenji
authors: K
authors: Jinnai
authors: Naonobu
authors: N
authors: Futamura
authors: Michio
authors: M
authors: Kobayashi
authors: Itaru
authors: I
authors: Toyoshima
authors: Toshiaki
authors: T
authors: Yoshioka
authors: Katsuhiko
authors: K
authors: Enomoto
authors: Nobutaka
authors: N
authors: Arai
authors: Yuko
authors: Y
authors: Saito
authors: Kunimasa
authors: K
authors: Arima
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000201:enzymology* / Q000378:metabolism; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000378:metabolism*; D008060:Lipodystrophy / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010009:Osteochondrodysplasias / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D013344:Subacute Sclerosing Panencephalitis / Q000201:enzymology* / Q000473:pathology; D000072377:Syk Kinase; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase