title: Activated caspase-9 immunoreactivity in glial and neuronal cytoplasmic inclusions in multiple system atrophy.
abstract: The mitochondria play an important role in apoptotic cell death, and the released cytochrome c from the mitochondria promotes the formation of the apoptosome, which contains cytochrome c, Apaf-1 and caspase-9, resulting in the activation of caspase-9 and the promotion of the apoptotic cascade. To investigate the role of mitochondria-dependent apoptotic cell death in patients with multiple system atrophy (MSA), we performed immunohistochemical studies on apoptosome-related proteins in formalin-fixed, paraffin-embedded sections from 8 normal subjects and 10 patients with MSA. We then performed double-labeling immunohistochemistry for activated caspase-9 and α-synuclein in some sections from 10 patients with MSA. In the brains with MSA, glial cytoplasmic inclusions (GCIs) and neuronal cytoplasmic inclusions (NCIs) were intensely immunoreactive for cytochrome c, Apaf-1 and caspase-9. Activated caspase-9 immunoreactivities were also confirmed to be densely localized to both GCIs and NCIs using two types of anti-cleaved caspase-9 antibodies. The semiquantitative analyses using the upper pontine sections double-immunostained with cleaved caspase-9 and α-synuclein demonstrated that approximately 80% of GCIs and NCIs were immunopositive for cleaved caspase-9. Our results suggest that the formation of the apoptosome accompanied by the activation of caspase-9 may occur in brains affected by MSA, and that a mitochondria-dependent apoptotic pathway may be partially associated with the pathogenesis of MSA.
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Neurology, Seijinkai Rakusaishimizu Hospital, Kyoto, Japan. Electronic address: kawamoto@kuhp.kyoto-u.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kawamoto
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ayaki
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Urushitani
authors.affiliation: Department of Neurology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
mesh_terms: D000368:Aged; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D053453:Caspase 9 / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000201:enzymology* / Q000473:pathology; D009457:Neuroglia / Q000201:enzymology* / Q000473:pathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology
chemical_list: C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D045304:Cytochromes c; D053453:Caspase 9
keywords: Apoptosome; Caspase-9; Glial cytoplasmic inclusions; Multiple system atrophy; Neuronal cytoplasmic inclusions