title: Absence of ubiquitinated inclusions in hypocretin neurons of patients with narcolepsy.
abstract: OBJECTIVE
  The cause of hypocretin cell loss in human narcolepsy-cataplexy is unknown but has been suggested to be neurodegenerative in nature. To test this hypothesis, we evaluated the remaining hypocretin cells in human narcolepsy brains for the presence of aggregated protein inclusions, gliosis, and inflammation.
  
  
  METHODS
  Brains were examined by routine histologic methods for potential comorbid neurodegenerative diseases and through immunohistochemical screening for protein inclusions in the hypothalamus. Hypothalamic sections of 4 subjects with narcolepsy and 5 nonneurologic controls were examined immunohistochemically with antibodies against ubiquitin (a marker of aggregated protein), allograft inflammatory factor 1 (AIF1, a microglial activation marker), glial fibrillary acidic protein (GFAP, a reactive astrocytic marker), and hypocretin. Hypothalami of subjects with narcolepsy were additionally examined for the presence of known components of protein aggregates (tau, alpha-synuclein, amyloid beta, and TDP-43).
  
  
  RESULTS
  Hypocretin cells were markedly decreased in all 4 subjects with narcolepsy. Ubiquitinated inclusions were not observed in the total of 96 remaining hypocretin cells in these subjects. Further, we noted that even in patients with dementia neuropathology, the lateral hypothalamic hypocretin area was spared from ubiquitinated inclusions. AIF1 and GFAP staining in the perifornical area was unremarkable.
  
  
  CONCLUSIONS
  Our findings suggest that hypocretin cell loss does not involve ubiquitinated inclusions, the hallmark of most neurodegenerative diseases. The lack of increased markers of inflammation also argues against a progressive and continuous neurodegenerative process.
authors.affiliation: Sleep Disorders Research Project, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan. honda@prit.go.jp
authors.forename: M
authors.initials: M
authors.lastname: Honda
authors.forename: T
authors.initials: T
authors.lastname: Arai
authors.forename: M
authors.initials: M
authors.lastname: Fukazawa
authors.forename: Y
authors.initials: Y
authors.lastname: Honda
authors.forename: K
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: A
authors.initials: A
authors.lastname: Salehi
authors.forename: H
authors.initials: H
authors.lastname: Akiyama
authors.forename: E
authors.initials: E
authors.lastname: Mignot
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D004660:Encephalitis / Q000473:pathology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000473:pathology; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008840:Microfilament Proteins; D009290:Narcolepsy / Q000473:pathology* / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000473:pathology* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins; D025801:Ubiquitin / Q000032:analysis / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology
chemical_list: C112986:AIF1 protein, human; D015415:Biomarkers; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D009479:Neuropeptides; D000068797:Orexins; D025801:Ubiquitin
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