title: Transgenic supplementation of SIRT1 fails to alleviate acute loss of nigrostriatal dopamine neurons and gliosis in a mouse model of MPTP-induced parkinsonism.
abstract: Background Dopamine (DA) neuron-selective uptake and toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans. Loss of DA neurons via mitochondrial damage and oxidative stress is reproduced by systemic injection of MPTP in animals, which serves as models of parkinsonism and Parkinson's disease (PD). This study aimed to test whether pan-neural supplementation of the longevity-related, pleiotropic deacetylase SIRT1, which confers partial tolerance to at least three models of stroke and neurodegeneration, could also alleviate MPTP-induced acute pathological changes in nigrostriatal DA neurons and neighboring glia. Results We employed a line of prion promoter-driven Sirt1-transgenic (Sirt1Tg) mice that chronically overexpress murine SIRT1 in the brain and spinal cord. Sirt1Tg and wild-type (WT) male littermates (3‒4 months old) were subjected to intraperitoneal injection of MPTP. Acute histopathological changes in the midbrain and striatum (caudoputamen) were assessed with serial coronal sections triply labeled for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and nuclear DNA. In the substantia nigra pars compacta (SNpc) of the midbrain, the number of TH-positive neurons and the reactive gliosis were comparable between the Sirt1Tg and WT littermates. In the striatum, the relative fluorescence intensity of TH-positive nerve terminals and the level of gliosis did not differ by the genotypes. Conclusions Sirt1Tg and WT littermate mice exhibited comparable acute histopathological reactions to the systemic injection of MPTP, loss of TH-positive neurons and reactive gliosis. Thus, the genetic supplementation of SIRT1 does not confer histologically recognizable protection on nigrostriatal DA neurons against acute toxicity of MPTP.
authors.affiliation: Department of Neuroanatomy, Kanazawa University, Takara-machi, Kanazawa, 920-8640, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kitao
authors.affiliation: Department of Molecular Biology, Division of Biological Sciences, Nagoya University Graduate School of Science, Furo-cho, Chikusa, Nagoya 464-8602, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Ageta-Ishihara
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, 606-8501, Japan ; Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Department of Molecular Biology, Division of Biological Sciences, Nagoya University Graduate School of Science, Furo-cho, Chikusa, Nagoya 464-8602, Japan ; Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kinoshita
authors.affiliation: Department of Neuroanatomy, Kanazawa University, Takara-machi, Kanazawa, 920-8640, Japan ; Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Hori
keywords: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); Dopamine; SIRT1; Sirtuin; resveratrol