(ADP-ribose) polymerase 1 and AMP-activated protein kinase mediate progressive dopaminergic neuronal degeneration in a mouse model of Parkinson's disease

T. W. Kim; H. M. Cho; S. Y. Choi; Y. Suguira; T. Hayasaka; M. Setou; H. C. Koh; E. Mi Hwang; J. Y. Park; S. J. Kang; H. S. Kim; H. Kim; W. Sun

doi:10.1038/cddis.2013.447

(ADP-ribose) polymerase 1 and AMP-activated protein kinase mediate progressive dopaminergic neuronal degeneration in a mouse model of Parkinson's disease

T. W. Kim, H. M. Cho, S. Y. Choi, Y. Suguira, T. Hayasaka, M. Setou, H. C. Koh, E. Mi Hwang, J. Y. Park, S. J. Kang, H. S. Kim, H. Kim, W. Sun

Department of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

78 Citations (Scopus)

Abstract

Genetic and epidemiologic evidence suggests that cellular energy homeostasis is critically associated with Parkinson's disease (PD) pathogenesis. Here we demonstrated that genetic deletion of Poly (ADP-ribose) polymerase 1 completely blocked 6-hydroxydopamine-induced dopaminergic neurodegeneration and related PD-like symptoms. Hyperactivation of PARP-1 depleted ATP pools in dopaminergic (DA) neurons, thereby activating AMP-activated protein kinase (AMPK). Further, blockade of AMPK activation by viral infection with dominant-negative AMPK strongly inhibited DA neuronal atrophy with moderate suppression of nuclear translocation of apoptosis-inhibiting factor (AIF), whereas overactivation of AMPK conversely strengthened the 6-OHDA-induced DA neuronal degeneration. Collectively, these results suggest that manipulation of PARP-1 and AMPK signaling is an effective therapeutic approach to prevent PD-related DA neurodegeneration.

Original language	English
Article number	e919
Journal	Cell Death and Disease
Volume	4
Issue number	11
DOIs	https://doi.org/10.1038/cddis.2013.447
Publication status	Published - 2013 Nov

Bibliographical note

Funding Information:
Acknowledgements. We thank Dr. Seong-Woon Yu and Dr. Han Seok Ko for critical review and thoughtful comments. This research was supported by the Brain Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2012M3A9C6049933, NRF-2011-0019212, and NRF-2010-0020237).

Keywords

6-OHDA
AMPK
ATP
PARP-1
Parkinson's disease

ASJC Scopus subject areas

Immunology
Cellular and Molecular Neuroscience
Cell Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/cddis.2013.447

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Kim, T. W., Cho, H. M., Choi, S. Y., Suguira, Y., Hayasaka, T., Setou, M., Koh, H. C., Mi Hwang, E., Park, J. Y., Kang, S. J., Kim, H. S., Kim, H., & Sun, W. (2013). (ADP-ribose) polymerase 1 and AMP-activated protein kinase mediate progressive dopaminergic neuronal degeneration in a mouse model of Parkinson's disease. Cell Death and Disease, 4(11), Article e919. https://doi.org/10.1038/cddis.2013.447

Kim, TW, Cho, HM, Choi, SY, Suguira, Y, Hayasaka, T, Setou, M, Koh, HC, Mi Hwang, E, Park, JY, Kang, SJ, Kim, HS, Kim, H & Sun, W 2013, '(ADP-ribose) polymerase 1 and AMP-activated protein kinase mediate progressive dopaminergic neuronal degeneration in a mouse model of Parkinson's disease', Cell Death and Disease, vol. 4, no. 11, e919. https://doi.org/10.1038/cddis.2013.447

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title = "(ADP-ribose) polymerase 1 and AMP-activated protein kinase mediate progressive dopaminergic neuronal degeneration in a mouse model of Parkinson's disease",

abstract = "Genetic and epidemiologic evidence suggests that cellular energy homeostasis is critically associated with Parkinson's disease (PD) pathogenesis. Here we demonstrated that genetic deletion of Poly (ADP-ribose) polymerase 1 completely blocked 6-hydroxydopamine-induced dopaminergic neurodegeneration and related PD-like symptoms. Hyperactivation of PARP-1 depleted ATP pools in dopaminergic (DA) neurons, thereby activating AMP-activated protein kinase (AMPK). Further, blockade of AMPK activation by viral infection with dominant-negative AMPK strongly inhibited DA neuronal atrophy with moderate suppression of nuclear translocation of apoptosis-inhibiting factor (AIF), whereas overactivation of AMPK conversely strengthened the 6-OHDA-induced DA neuronal degeneration. Collectively, these results suggest that manipulation of PARP-1 and AMPK signaling is an effective therapeutic approach to prevent PD-related DA neurodegeneration.",

keywords = "6-OHDA, AMPK, ATP, PARP-1, Parkinson's disease",

author = "Kim, {T. W.} and Cho, {H. M.} and Choi, {S. Y.} and Y. Suguira and T. Hayasaka and M. Setou and Koh, {H. C.} and {Mi Hwang}, E. and Park, {J. Y.} and Kang, {S. J.} and Kim, {H. S.} and H. Kim and W. Sun",

note = "Funding Information: Acknowledgements. We thank Dr. Seong-Woon Yu and Dr. Han Seok Ko for critical review and thoughtful comments. This research was supported by the Brain Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2012M3A9C6049933, NRF-2011-0019212, and NRF-2010-0020237).",

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doi = "10.1038/cddis.2013.447",

language = "English",

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AU - Kim, T. W.

AU - Cho, H. M.

AU - Choi, S. Y.

AU - Suguira, Y.

AU - Hayasaka, T.

AU - Setou, M.

AU - Koh, H. C.

AU - Mi Hwang, E.

AU - Park, J. Y.

AU - Kang, S. J.

AU - Kim, H. S.

AU - Kim, H.

AU - Sun, W.

N1 - Funding Information: Acknowledgements. We thank Dr. Seong-Woon Yu and Dr. Han Seok Ko for critical review and thoughtful comments. This research was supported by the Brain Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2012M3A9C6049933, NRF-2011-0019212, and NRF-2010-0020237).

PY - 2013/11

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N2 - Genetic and epidemiologic evidence suggests that cellular energy homeostasis is critically associated with Parkinson's disease (PD) pathogenesis. Here we demonstrated that genetic deletion of Poly (ADP-ribose) polymerase 1 completely blocked 6-hydroxydopamine-induced dopaminergic neurodegeneration and related PD-like symptoms. Hyperactivation of PARP-1 depleted ATP pools in dopaminergic (DA) neurons, thereby activating AMP-activated protein kinase (AMPK). Further, blockade of AMPK activation by viral infection with dominant-negative AMPK strongly inhibited DA neuronal atrophy with moderate suppression of nuclear translocation of apoptosis-inhibiting factor (AIF), whereas overactivation of AMPK conversely strengthened the 6-OHDA-induced DA neuronal degeneration. Collectively, these results suggest that manipulation of PARP-1 and AMPK signaling is an effective therapeutic approach to prevent PD-related DA neurodegeneration.

AB - Genetic and epidemiologic evidence suggests that cellular energy homeostasis is critically associated with Parkinson's disease (PD) pathogenesis. Here we demonstrated that genetic deletion of Poly (ADP-ribose) polymerase 1 completely blocked 6-hydroxydopamine-induced dopaminergic neurodegeneration and related PD-like symptoms. Hyperactivation of PARP-1 depleted ATP pools in dopaminergic (DA) neurons, thereby activating AMP-activated protein kinase (AMPK). Further, blockade of AMPK activation by viral infection with dominant-negative AMPK strongly inhibited DA neuronal atrophy with moderate suppression of nuclear translocation of apoptosis-inhibiting factor (AIF), whereas overactivation of AMPK conversely strengthened the 6-OHDA-induced DA neuronal degeneration. Collectively, these results suggest that manipulation of PARP-1 and AMPK signaling is an effective therapeutic approach to prevent PD-related DA neurodegeneration.

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KW - ATP

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(ADP-ribose) polymerase 1 and AMP-activated protein kinase mediate progressive dopaminergic neuronal degeneration in a mouse model of Parkinson's disease

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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