Accumulation of HtrA2/Omi in neuronal and glial inclusions in brains with alpha-synucleinopathies.
HtrA2/Omi is a mitochondrial serine protease that is released into the cytosol and promotes apoptotic processes by binding to several members of the inhibitors of apoptosis protein family. HtrA2/Omi knockout mice show a parkinsonian phenotype, and mutations in the gene encoding HtrA2/Omi have been identified as susceptibility factors for Parkinson disease (PD). These results suggest that HtrA2/Omi may be involved in the pathogenesis of PD. We performed immunohistochemical studies of HtrA2/Omi on brains from patients with alpha-synuclein-related disorders, including PD, dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA); patients with other neurodegenerative diseases; and controls. HtrA2/Omi is expressed in normal brain tissue, and there was some anti-HtrA2/Omi immunostaining of neurons in normal brains as well as those with other neurodegenerative diseases. In PD and DLB brains, both classic (i.e. brainstem-type) and cortical Lewy bodies were intensely immunostained; pale bodies were also strongly immunopositive for HtrA2/Omi. In MSA brains, numerous glial cytoplasmic inclusions, neuronal cytoplasmic inclusions, and dystrophic neurites were also intensely immunoreactive for HtrA2/Omi. These results suggest that widespread accumulation of HtrA2/Omi may occur in pathologic alpha-synuclein-containing inclusions in brains with PD, DLB, or MSA and that HtrA2/Omi may be associated with the pathogenesis of alpha-synucleinopathies.
Kawamoto
Yasuhiro
Y
Department of Neurology, Faculty of Medicine, Kyoto University, and Department of Neurology, Seijinnkai Rakusaisimizu Hospital, Kyoto, Japan. kawamoto@kuhp.kyoto-u.ac.jp
Kobayashi
Yoshito
Y
Suzuki
Yasuyuki
Y
Inoue
Haruhisa
H
Tomimoto
Hidekazu
H
Akiguchi
Ichiro
I
Budka
Herbert
H
Martins
L Miguel
LM
Downward
Julian
J
Takahashi
Ryosuke
R
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001344:Autopsy; D015153:Blotting, Western; D001921:Brain / Q000473:pathology*; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology*; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism*; D016631:Lewy Bodies / Q000235:genetics / Q000473:pathology; D020961:Lewy Body Disease / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D019578:Multiple System Atrophy / Q000473:pathology; D009422:Nervous System Diseases / Q000235:genetics / Q000473:pathology*; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000473:pathology; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000502:physiology*
D024101:Mitochondrial Proteins; D051844:alpha-Synuclein; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse