Absence of ubiquitinated inclusions in hypocretin neurons of patients with narcolepsy.
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.
Honda
M
M
Sleep Disorders Research Project, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan. honda@prit.go.jp
Arai
T
T
Fukazawa
M
M
Honda
Y
Y
Tsuchiya
K
K
Salehi
A
A
Akiyama
H
H
Mignot
E
E
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
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
Ann Neurol. 2008 Jul;64(1):60-70
18546284
Sleep. 2006 May;29(5):601-2
16774147
Sci Aging Knowledge Environ. 2003 Aug 27;2003(34):RE6
12944592
Acta Neuropathol. 2007 Jan;113(1):75-80
17089135
Neuron. 2000 Sep;27(3):415-8
11055422
Brain. 2007 Jun;130(Pt 6):1577-85
17470494
Science. 2006 Oct 6;314(5796):130-3
17023659
Neurosci Lett. 1987 Mar 9;74(3):364-70
2436113
Biochem Biophys Res Commun. 1993 Mar 15;191(2):392-8
8460999
Neurology. 1991 Apr;41(4):479-86
2011243
Neurology. 2005 Oct 25;65(8):1184-8
16247044
Acta Neuropathol. 1991;82(4):239-59
1759558
Nat Med. 2000 Sep;6(9):991-7
10973318
Brain. 1995 Feb;118 ( Pt 1):119-29
7894998
Exp Neurol. 2008 Apr;210(2):409-20
18164295
Neuron. 2000 Sep;27(3):469-74
11055430
Biochem Biophys Res Commun. 2006 Dec 22;351(3):602-11
17084815
Brain. 2007 Jun;130(Pt 6):1586-95
17491094
FEBS Lett. 1996 Apr 8;384(1):25-30
8797796
Hum Mol Genet. 2005 Jan 1;14(1):39-47
15525658
Nat Med. 2004 Jul;10 Suppl:S10-7
15272267