Enhancement of adult neurogenesis for Parkisnon's diseased primate models

• Project/Area Number: 16390255
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Juntendo University
• Principal Investigator: MOCHIZUKI Hideki Juntendo University, Dept.of Neurology, Associate professor, 医学部, 助教授 (90230044)
• Co-Investigator(Kenkyū-buntansha): FUNAKOSHI Hiroshi Osaka University, Department of Biochemistry and Molecular Biology, Associate professor, 大学院・医学研究科, 助教授 (40273685) ; TAKADA Masahiko Tokyo Metropolitan Institute for Neuroscience, Department of System Neuroscience, Project leader, 東京都神経科学総合研究所, 副参事研究員 (00236233) ; MIZUNO Yoshikuni Juntendo University, Dept.of Neurology, Professor, 医学部, 教授 (30049043)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥14,300,000 (Direct Cost: ¥14,300,000); Fiscal Year 2005: ¥6,900,000 (Direct Cost: ¥6,900,000); Fiscal Year 2004: ¥7,400,000 (Direct Cost: ¥7,400,000)
• Keywords: Parkinson's disease / Regeneration medicine / Hepatocyte growth factor / MPTP / Neuronal stem cell / Retrovirus vector / 幹細胞 / HGF / MTPT / 神経栄養因子 / レトロウイルス / 猿

Research Abstract

The possibility for the neurogenesis of nigral neurons was examinedin animals and autopsy brains including those of patients with PD. First, proliferating cells in the SN were labeled efficiently with retroviral transfection of green fluorescent protein (GFP). The subsequent differentiation of labelled cells followed, in which many transfected cells became microglia but none had differentiated into tyrosine hydroxylase (TH)-positive neurons at 4 weeks post transfection in both intact and MPTP-treated rodents. Our result indicated that retroviral labelling in rodents indicated a lack of neurogenesis of TH-positive neurons from proliferative stem/progenitor cells in the SN. Second, polysialic acid (PSA)-like immunoreactivity, which was indicative of newly differentiated neurons, was detected in the SN of rodents, primate and human midbrains. A large number of PSA-positive cells were detected in the SN pars reticulata of some patients with PD.
It has been suggested that certain therapeutic agents currently in use, such as selegiline, ropinirole and pramipexole, can slow the progress of the disease. In this regard, a recent study showed that dopaminergic agonists stimulate neurogenesis in SVZ. Further studies need to be conducted in order to examine the effects of these compounds on neurogenesis in the midbrain. This findings were published in Ann Neurol.58(1):31-40,2005. It was sited in Reuters (2005.7.22)、Daily Yomiuri (2005.7.26) and Daily Mainichi (2005.8.15).
To identify this hypothesis, we examined the effect of hepatocyte growth factor (HGF) using Parkinson's diseased models. At first, we created MPTP treated Parkinson's disease primate model. Using the infusion pump, HGF was continuously injected into the striatum in PD primate models. Unfortunately, we could not detect the pathological changes and clinical benefits in the treated PD models. We are going to examine the new compounds to upregulate the PSA positive cells in our models. (291 words)

Research Products

• [Journal Article] Characterization of multimetric variants of ubiquitin carboxyl-terminal Hydrolase L1 in water by small-angle neutron scattering. (2006)
  • Author(s): Naito S, Mochizuki H, Yasuda T, Mizuno Y, Furusaka M, Ikeda S, Adachi T, Shimizu H, Suzuki J, Fujiwara S, Okada T, Nishikawa K, Aoki S, Wada K
  • Journal Title: Biochem Biophys Res Commun 339(2) Pages: 717-725
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Down-regulation of alpha-synuclein expression can rescue dopaminergic cells from cell death in the substantia nigra of Parkinson's disease rat model. (2006)
  • Author(s): Hayashita-Kinoh H, Yamada M, Yokota T, Mizuno Y, Mochizuki H
  • Journal Title: Biochem Biophys Res Commun Mar 24; 341(4) Pages: 1088-95
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Characterization of multimetric variants of ubiquitin carboxyl-terminal Hydrolase L1 in water by small-angle neutron scattering. (2006)
  • Author(s): Naito S, Mochizuk H, Yasuda T, Mizuno Y, Furusaka M, Ikeda S, Adachi T, Shimizu H, Suzuki J, Fujiwara S, Okada T, Nishikawa K, Aoki S, Wada K
  • Journal Title: Biochem Biophys Res Commun 339(2) Pages: 717-725
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Down-regulation of alpha-synuclein expression can rescue dopaminergic cells from cell death in the substantia nigra of Parkinson's disease rat model. (2006)
  • Author(s): Hayashita-Kinoh H, Yamada M, Yokota T, Mizuno Y, Mochizuki H.
  • Journal Title: Biochem Biophys Res Commun. 341(4) Pages: 1088-1095
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Down-regulation of alpha-synuclein expression can rescue dopaminergic cells from cell death in the substantia nigra of Parkinson's disease rat model. (2006)
  • Author(s): Hayashita-Kinoh H, Yamada M, Yokota T, Mizuno Y, Mochizuki H
  • Journal Title: Biochem Biophys Res Commun. Mar 24;341(4) Pages: 1088-1095
• [Journal Article] Pro-apoptotic protein glyceraldehyde-3-phosphate dehydrogenase promotes the formation of Lewy body-like inclusions. (2005)
  • Author(s): Tsuchiya K, Tajima H, Kuwae T, Takeshima T, Nakano T, Tanaka M, Sunaga K, Fukuhara Y, Nakashima K, Ohama E, Mochizuki H, Mizuno Y, Katsube N, Ishitani R.
  • Journal Title: Eur J Neurosci Jan; 21(2) Pages: 317-26
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Parkin inhibits alpha-synucleinopathy in rat substantia nigra. (2005)
  • Author(s): Yamada M, Iwatsubo T, Mizuno Y, Mochizuki H.
  • Journal Title: Hum Gene Ther. Feb; 16(2) Pages: 262-70
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Possibility for neurogenesis in substantia nigra of parkinsonian brain. (2005)
  • Author(s): Yoshimi K, Ren YR, Seki T, Yamada M, Ooizumi H, Onodera M, Saito Y, Murayama S, Okano H, Mizuno Y, Mochizuki H.
  • Journal Title: Ann Neurol. Jul; 58(1) Pages: 31-40
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Pro-apoptotic protein glyceraldehyde-3-phosphate dehydrogenase promotes the formation of Lewy body-like inclusions. (2005)
  • Author(s): Tsuchiya K, Tajima H, Kuwae T, Takeshima T, Nakano T, Tanaka M, Sunaga K, Fukuhara Y, Nakashima K, Ohama E, Mochizuki H. Mizuno Y, Katsube N, Ishitani R
  • Journal Title: Eur J Neurosci. 21(2) Pages: 317-326
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Parkin inhibits alpha-synucleinopathy in rat substantia nigra. (2005)
  • Author(s): Yamada M, Iwatsubo T, Mizuno Y, Mochizuki H.
  • Journal Title: Human Gene Therapy 16 Pages: 262-270
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Possibility for neurogenesis in substantia nigra of parkinsonian brain. (2005)
  • Author(s): Yoshimi K, Ren YR, Seki T, Yamada M, Ooizumi H, Onodera M, Saito Y, Murayama S, Okano H, Mizuno Y, Mochizuki H.
  • Journal Title: Ann Neurol. 58(1) Pages: 31-40
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Pro-apoptotic protein glyceraldehyde-3-phosphate dehydrogenase promotes the formation of Lewy body-like inclusions. (2005)
  • Author(s): Tsuchiya K, Tajima H, Kuwae T, Takeshima T, Nakano T, Tanaka M, Sunaga K, Fukuhara Y, Nakashima K, Ohama E, Mochizuki H, Mizuno Y, Katsube N, Ishitani R.
  • Journal Title: Eur J Neurosci. Jan;21(2) Pages: 317-326
• [Journal Article] Parkin inhibits alpha-synucleinopathy in rat substantia nigra. (2005)
  • Author(s): Yamada M, Iwatsubo T, Mizuno Y, Mochizuki H.
  • Journal Title: Hum Gene Ther. Feb;16(2) Pages: 262-270
• [Journal Article] Possibility for neurogenesis in substantia nigra of parkinsonian brain. (2005)
  • Author(s): Yoshimi K, Ren YR, Seki T, Yamada M, Ooizumi H, Onodera M, Saito Y, Murayama S, Okano H, Mizuno Y, Mochizuki H.
  • Journal Title: Ann Neurol. Jul;58(1) Pages: 31-40
• [Journal Article] Neurogenesis in olfactory bulb identified by retroviral labeling in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated adult mice. (2004)
  • Author(s): Yamada M, Onodera M, Mizuno Y, Mochizuki H.
  • Journal Title: Neuroscience. 124 Pages: 173-181
• [Journal Article] Dual role of Fcgamma receptor in transient focal cerebral ischemia in mice. (2004)
  • Author(s): Komine M, Chou N, Mochizuki H, Nakao A, Mizuno Y, Urabe T.
  • Journal Title: Stroke 35(4) Pages: 958-963
• [Journal Article] Neurogenesis After Transient Global Ischemia in the Adult Hippocampus Visualized by Improved Retroviral Vector. (2004)
  • Author(s): Tanaka R, Yamashiro K, Mochizuki H, Cho N, Onodera M, Mizuno Y, Ur
  • Journal Title: Stroke. 35(6) Pages: 1454-1459
• [Journal Article] Functional Effects of NAD(P)H Oxidase p22phox C242T Mutation in Human Leukocytes and Association with Thrombotic Cerebral Infarction. (2004)
  • Author(s): Shimo Y, Hasebe T, Suzuki A, Mochizuki H, Tanaka Y, Nagaoka I, Mizuno Y, Urabe T.
  • Journal Title: Atherosclerosis: 175 Pages: 109-115
• [Journal Article] Overexpression of α-synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation of α-synuclein and activation of caspase (2004)
  • Author(s): Yamada M, Iwatsubo T, Mizuno Y, Mochizuki H.
  • Journal Title: Neurochem 91 Pages: 451-161
• [Journal Article] Neurotoxic effects of lipopolysaccharide on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1b, and expression of caspase-11 in mice. (2004)
  • Author(s): Arai H, Furuya T, Miura M, Mizuno Y, Mochizuki H.
  • Journal Title: J Biol Chem 79 Pages: 51647-51653
• [Book] Neuroprotection. In Treatment of Parkinson's disease. Shapira AHV and Olanow CW, (Ed)Woburn (2006)
  • Author(s): Mochizuki H, Mizuno Y
  • Publisher: Elsevier Science Publishers(In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Treatment of Parkinson's disease. "Neuroprotection." (Shapira AHV and Olanow CW, (Ed)) (2006)
  • Author(s): Mochizuki H, Mizuno Y
  • Publisher: Elsevier Science Publishers, Woburn (In press)