Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue

Yoichi Imaizumi, Yohei Okada, Wado Akamatsu, Masato Koike, Naoko Kuzumaki, Hideki Hayakawa, Tomoko Nihira, Tetsuro Kobayashi, Manabu Ohyama, Shigeto Sato, Masashi Takanashi, Manabu Funayama, Akiyoshi Hirayama, Tomoyoshi Soga, Takako Hishiki, Makoto Suematsu, Takuya Yagi, Daisuke Ito, Arifumi Kosakai, Kozo HayashiMasanobu Shouji, Atsushi Nakanishi, Norihiro Suzuki, Yoshikuni Mizuno, Noboru Mizushima, Masayuki Amagai, Yasuo Uchiyama, Hideki Mochizuki, Nobutaka Hattori, Hideyuki Okano

Research output: Contribution to journalArticle

202 Citations (Scopus)

Abstract

Background: Parkinson's disease (PD) is a neurodegenerative disease characterized by selective degeneration of dopaminergic neurons in the substantia nigra (SN). The familial form of PD, PARK2, is caused by mutations in the parkin gene. parkin-knockout mouse models show some abnormalities, but they do not fully recapitulate the pathophysiology of human PARK2. Results: Here, we generated induced pluripotent stem cells (iPSCs) from two PARK2 patients. PARK2 iPSC-derived neurons showed increased oxidative stress and enhanced activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. iPSC-derived neurons, but not fibroblasts or iPSCs, exhibited abnormal mitochondrial morphology and impaired mitochondrial homeostasis. Although PARK2 patients rarely exhibit Lewy body (LB) formation with an accumulation of α-synuclein, α-synuclein accumulation was observed in the postmortem brain of one of the donor patients. This accumulation was also seen in the iPSC-derived neurons in the same patient. Conclusions: Thus, pathogenic changes in the brain of a PARK2 patient were recapitulated using iPSC technology. These novel findings reveal mechanistic insights into the onset of PARK2 and identify novel targets for drug screening and potential modified therapies for PD.

Original languageEnglish
Article number35
JournalMolecular Brain
Volume5
Issue number1
DOIs
Publication statusPublished - 2012

Fingerprint

Synucleins
Induced Pluripotent Stem Cells
Oxidative Stress
Neurons
Brain
Parkinson Disease
Lewy Bodies
Preclinical Drug Evaluations
Dopaminergic Neurons
Substantia Nigra
Knockout Mice
Neurodegenerative Diseases
Homeostasis
Fibroblasts
Tissue Donors
Technology
Mutation

Keywords

  • α-synuclein
  • Induced pluripotent stem cells
  • Mitochondria
  • Oxidative stress
  • Parkin
  • Parkinson's disease

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Molecular Biology

Cite this

Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue. / Imaizumi, Yoichi; Okada, Yohei; Akamatsu, Wado; Koike, Masato; Kuzumaki, Naoko; Hayakawa, Hideki; Nihira, Tomoko; Kobayashi, Tetsuro; Ohyama, Manabu; Sato, Shigeto; Takanashi, Masashi; Funayama, Manabu; Hirayama, Akiyoshi; Soga, Tomoyoshi; Hishiki, Takako; Suematsu, Makoto; Yagi, Takuya; Ito, Daisuke; Kosakai, Arifumi; Hayashi, Kozo; Shouji, Masanobu; Nakanishi, Atsushi; Suzuki, Norihiro; Mizuno, Yoshikuni; Mizushima, Noboru; Amagai, Masayuki; Uchiyama, Yasuo; Mochizuki, Hideki; Hattori, Nobutaka; Okano, Hideyuki.

In: Molecular Brain, Vol. 5, No. 1, 35, 2012.

Research output: Contribution to journalArticle

Imaizumi, Y, Okada, Y, Akamatsu, W, Koike, M, Kuzumaki, N, Hayakawa, H, Nihira, T, Kobayashi, T, Ohyama, M, Sato, S, Takanashi, M, Funayama, M, Hirayama, A, Soga, T, Hishiki, T, Suematsu, M, Yagi, T, Ito, D, Kosakai, A, Hayashi, K, Shouji, M, Nakanishi, A, Suzuki, N, Mizuno, Y, Mizushima, N, Amagai, M, Uchiyama, Y, Mochizuki, H, Hattori, N & Okano, H 2012, 'Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue', Molecular Brain, vol. 5, no. 1, 35. https://doi.org/10.1186/1756-6606-5-35
Imaizumi, Yoichi ; Okada, Yohei ; Akamatsu, Wado ; Koike, Masato ; Kuzumaki, Naoko ; Hayakawa, Hideki ; Nihira, Tomoko ; Kobayashi, Tetsuro ; Ohyama, Manabu ; Sato, Shigeto ; Takanashi, Masashi ; Funayama, Manabu ; Hirayama, Akiyoshi ; Soga, Tomoyoshi ; Hishiki, Takako ; Suematsu, Makoto ; Yagi, Takuya ; Ito, Daisuke ; Kosakai, Arifumi ; Hayashi, Kozo ; Shouji, Masanobu ; Nakanishi, Atsushi ; Suzuki, Norihiro ; Mizuno, Yoshikuni ; Mizushima, Noboru ; Amagai, Masayuki ; Uchiyama, Yasuo ; Mochizuki, Hideki ; Hattori, Nobutaka ; Okano, Hideyuki. / Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue. In: Molecular Brain. 2012 ; Vol. 5, No. 1.
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abstract = "Background: Parkinson's disease (PD) is a neurodegenerative disease characterized by selective degeneration of dopaminergic neurons in the substantia nigra (SN). The familial form of PD, PARK2, is caused by mutations in the parkin gene. parkin-knockout mouse models show some abnormalities, but they do not fully recapitulate the pathophysiology of human PARK2. Results: Here, we generated induced pluripotent stem cells (iPSCs) from two PARK2 patients. PARK2 iPSC-derived neurons showed increased oxidative stress and enhanced activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. iPSC-derived neurons, but not fibroblasts or iPSCs, exhibited abnormal mitochondrial morphology and impaired mitochondrial homeostasis. Although PARK2 patients rarely exhibit Lewy body (LB) formation with an accumulation of α-synuclein, α-synuclein accumulation was observed in the postmortem brain of one of the donor patients. This accumulation was also seen in the iPSC-derived neurons in the same patient. Conclusions: Thus, pathogenic changes in the brain of a PARK2 patient were recapitulated using iPSC technology. These novel findings reveal mechanistic insights into the onset of PARK2 and identify novel targets for drug screening and potential modified therapies for PD.",
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T1 - Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue

AU - Imaizumi, Yoichi

AU - Okada, Yohei

AU - Akamatsu, Wado

AU - Koike, Masato

AU - Kuzumaki, Naoko

AU - Hayakawa, Hideki

AU - Nihira, Tomoko

AU - Kobayashi, Tetsuro

AU - Ohyama, Manabu

AU - Sato, Shigeto

AU - Takanashi, Masashi

AU - Funayama, Manabu

AU - Hirayama, Akiyoshi

AU - Soga, Tomoyoshi

AU - Hishiki, Takako

AU - Suematsu, Makoto

AU - Yagi, Takuya

AU - Ito, Daisuke

AU - Kosakai, Arifumi

AU - Hayashi, Kozo

AU - Shouji, Masanobu

AU - Nakanishi, Atsushi

AU - Suzuki, Norihiro

AU - Mizuno, Yoshikuni

AU - Mizushima, Noboru

AU - Amagai, Masayuki

AU - Uchiyama, Yasuo

AU - Mochizuki, Hideki

AU - Hattori, Nobutaka

AU - Okano, Hideyuki

PY - 2012

Y1 - 2012

N2 - Background: Parkinson's disease (PD) is a neurodegenerative disease characterized by selective degeneration of dopaminergic neurons in the substantia nigra (SN). The familial form of PD, PARK2, is caused by mutations in the parkin gene. parkin-knockout mouse models show some abnormalities, but they do not fully recapitulate the pathophysiology of human PARK2. Results: Here, we generated induced pluripotent stem cells (iPSCs) from two PARK2 patients. PARK2 iPSC-derived neurons showed increased oxidative stress and enhanced activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. iPSC-derived neurons, but not fibroblasts or iPSCs, exhibited abnormal mitochondrial morphology and impaired mitochondrial homeostasis. Although PARK2 patients rarely exhibit Lewy body (LB) formation with an accumulation of α-synuclein, α-synuclein accumulation was observed in the postmortem brain of one of the donor patients. This accumulation was also seen in the iPSC-derived neurons in the same patient. Conclusions: Thus, pathogenic changes in the brain of a PARK2 patient were recapitulated using iPSC technology. These novel findings reveal mechanistic insights into the onset of PARK2 and identify novel targets for drug screening and potential modified therapies for PD.

AB - Background: Parkinson's disease (PD) is a neurodegenerative disease characterized by selective degeneration of dopaminergic neurons in the substantia nigra (SN). The familial form of PD, PARK2, is caused by mutations in the parkin gene. parkin-knockout mouse models show some abnormalities, but they do not fully recapitulate the pathophysiology of human PARK2. Results: Here, we generated induced pluripotent stem cells (iPSCs) from two PARK2 patients. PARK2 iPSC-derived neurons showed increased oxidative stress and enhanced activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. iPSC-derived neurons, but not fibroblasts or iPSCs, exhibited abnormal mitochondrial morphology and impaired mitochondrial homeostasis. Although PARK2 patients rarely exhibit Lewy body (LB) formation with an accumulation of α-synuclein, α-synuclein accumulation was observed in the postmortem brain of one of the donor patients. This accumulation was also seen in the iPSC-derived neurons in the same patient. Conclusions: Thus, pathogenic changes in the brain of a PARK2 patient were recapitulated using iPSC technology. These novel findings reveal mechanistic insights into the onset of PARK2 and identify novel targets for drug screening and potential modified therapies for PD.

KW - α-synuclein

KW - Induced pluripotent stem cells

KW - Mitochondria

KW - Oxidative stress

KW - Parkin

KW - Parkinson's disease

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