title: LC3, an autophagosome marker, is expressed on oligodendrocytes in Nasu-Hakola disease brains.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  By immunohistochemistry, we studied the expression of microtubule-associated protein 1 light chain 3 (LC3), an autophagosome marker, in 5 NHD and 12 control brains.
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  These results propose a novel hypothesis that aberrant regulation of autophagy might induce oligodendrogliopathy causative of leukoencephalopathy in NHD brains.
authors.affiliation: Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo, Japan. satoj@my-pharm.ac.jp.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Satoh
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Motohashi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kino
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ishida
authors.forename: Saburo
authors.initials: S
authors.lastname: Yagishita
authors.forename: Kenji
authors.initials: K
authors.lastname: Jinnai
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Arai
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Nakamagoe
authors.forename: Akira
authors.initials: A
authors.lastname: Tamaoka
authors.forename: Yuko
authors.initials: Y
authors.lastname: Saito
authors.forename: Kunimasa
authors.initials: K
authors.lastname: Arima
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008060:Lipodystrophy / Q000378:metabolism*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008875:Middle Aged; D009836:Oligodendroglia / Q000378:metabolism*; D010009:Osteochondrodysplasias / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism*; D013344:Subacute Sclerosing Panencephalitis / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins