Absence of ubiquitinated inclusions in hypocretin neurons of patients with narcolepsy.

Full Abstract

OBJECTIVES: 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.

Author information

Author/s: Honda, M (M); Arai, T (T); Fukazawa, M (M); Honda, Y (Y); Tsuchiya, K (K); Salehi, A (A); Akiyama, H (H); Mignot, E (E);

Affiliation: Sleep Disorders Research Project, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan. honda(-atsign-)prit.go.jp

Grants: 23724 (Agency:PHS HHS) ; MH080957 (Agency:NIMH NIH HHS) ; NS062798 (Agency:NINDS NIH HHS) ; (Agency:Howard Hughes Medical Institute)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Neurology (Neurology), published in United States. (Language: eng)

Reference: 2009-Aug; vol 73 (issue 7) : pp 511-7

Dates: Created 2009/08/18; Completed 2009/09/18;

PMID: 19687452, status: MEDLINE (last retrieved date: 9/18/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Aged
Aged, 80 and over
Biological Markers - analysis; metabolism
DNA-Binding Proteins - metabolism
Encephalitis - pathology
Female
Glial Fibrillary Acidic Protein - metabolism
Gliosis - pathology
Humans
Hypothalamus - metabolism; pathology; physiopathology

Hypothalamus - metabolism; pathology; physiopathology
Inclusion Bodies - metabolism; pathology
Intracellular Signaling Peptides and Proteins - metabolism
Male
Narcolepsy - pathology; physiopathology
Neurodegenerative Diseases - pathology; physiopathology
Neurons - metabolism; pathology
Neuropeptides - metabolism
Ubiquitin - analysis; metabolism
Ubiquitination - physiology

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: AIF1 protein, human (0) ; Biological Markers (0) ; DNA-Binding Proteins (0) ; Glial Fibrillary Acidic Protein (0) ; Intracellular Signaling Peptides and Proteins (0) ; Neuropeptides (0) ; Ubiquitin (0) ; orexins (0)

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