Absence of ubiquitinated inclusions in hypocretin neurons of patients with narcolepsy
- 18 August 2009
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Neurology
- Vol. 73 (7), 511-517
- https://doi.org/10.1212/wnl.0b013e3181b2a6af
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, α-synuclein, amyloid β, 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.Keywords
This publication has 23 references indexed in Scilit:
- Phosphorylated TDP‐43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosisAnnals of Neurology, 2008
- Hypocretin (orexin) loss in Parkinson's diseaseBrain, 2007
- TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosisBiochemical and Biophysical Research Communications, 2006
- Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral SclerosisScience, 2006
- Protein aggregation and neurodegenerative diseaseNature Medicine, 2004
- Ubiquitin, Proteasomes, and the Aging BrainScience of Aging Knowledge Environment, 2003
- Characterization of mAb AP422, a novel phosphorylation‐dependent monoclonal antibody against tau proteinFEBS Letters, 1996
- Secretory Form of Alzheimer Amyloid Precursor Protein 695 in Human Brain Lacks β/A4 Amyloid ImmunoreactivityBiochemical and Biophysical Research Communications, 1993
- Neuropathological stageing of Alzheimer-related changesActa Neuropathologica, 1991
- Hypothalamic pathology in Alzheimer's diseaseNeuroscience Letters, 1987