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

Kim, T W; Cho, H M; Choi, So Yoon; Suguira, Y; Hayasaka, Takahiro; Setou, Mitsutoshi; H, Koh; Hwang, Eun Mi; Park, Jae Yong; Kang, Seok-Jίn; Kim, H S; Kim, H; Sun, Woong

doi:10.1038/cddis.2013.447

Cited by 87 publications

(59 citation statements)

References 60 publications

(70 reference statements)

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“…S7). These findings are in agreement with a previous report that blockade of AMPK activation by the expression of AMPK-DN strongly inhibits DA neuron atrophy with moderate suppression of apoptosis and that overactivation of AMPK conversely strengthens DA neuronal degeneration induced by 6-hydroxydopamine (6-OHDA) (39). Furthermore, suppression of AMPK activity, either pharmacologically or genetically, exerts neuroprotective effects in cerebral ischemia (9,40).…”

Section: Discussionsupporting

confidence: 93%

α-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation

Kang

Zhang

Liu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The abnormal aggregation of fibrillar α-synuclein in Lewy bodies plays a critical role in the pathogenesis of Parkinson's disease. However, the molecular mechanisms regulating α-synuclein pathological effects are incompletely understood. Here we show that α-synuclein binds phosphoinositide-3 kinase enhancer L (PIKE-L) in a phosphorylationdependent manner and sequesters it in Lewy bodies, leading to dopaminergic cell death via AMP-activated protein kinase (AMPK) hyperactivation. α-Synuclein interacts with PIKE-L, an AMPK inhibitory binding partner, and this action is increased by S129 phosphorylation through AMPK and is decreased by Y125 phosphorylation via Src family kinase Fyn. A pleckstrin homology (PH) domain in PIKE-L directly binds α-synuclein and antagonizes its aggregation. Accordingly, PIKE-L overexpression decreases dopaminergic cell death elicited by 1-methyl-4-phenylpyridinium (MPP + ), whereas PIKE-L knockdown elevates α-synuclein oligomerization and cell death. The overexpression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or α-synuclein induces greater dopaminergic cell loss and more severe motor defects in PIKE-KO and Fyn-KO mice than in wild-type mice, and these effects are attenuated by the expression of dominant-negative AMPK. Hence, our findings demonstrate that α-synuclein neutralizes PIKE-L's neuroprotective actions in synucleinopathies, triggering dopaminergic neuronal death by hyperactivating AMPK.neurodegenerative disease | dopamine | Lewy bodies

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Section: Discussionsupporting

confidence: 93%

α-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation

Kang

Zhang

Liu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Similarly, treatment of mice with metformin following 6-OHDA, increased nuclear translocation of AIF, decreased TH intensity in the SNc, increased cellular atrophy, and decreased the number of SNc DA neurons. Expression of AMPK-DN ameliorated all of these effects, substantially reducing neuronal atrophy and modestly decreasing PCD [202]. …”

Section: Ampk Activation As a Treatment Strategy For Pdmentioning

confidence: 99%

“…The inhibition of cell growth pathways by AMPK may also promote neurodegeneration. Sustained AMPK activation may be detrimental by locking cells into a state of atrophy and preventing cellular regrowth following a severe but not necessarily lethal stressor [202]. …”

Section: Ampk Activation As a Treatment Strategy For Pdmentioning

confidence: 99%

Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson’s Disease

Curry

Stutz

Andrews

et al. 2018

JPD

113

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It is characterized by the accumulation of intracellular α-synuclein aggregates and the degeneration of nigrostriatal dopaminergic neurons. While no treatment strategy has been proven to slow or halt the progression of the disease, there is mounting evidence from preclinical PD models that activation of 5’-AMP-activated protein kinase (AMPK) may have broad neuroprotective effects. Numerous dietary supplements and pharmaceuticals (e.g. metformin) that increase AMPK activity are available for use in humans, but clinical studies of their effects in PD patients are limited. AMPK is an evolutionarily conserved serine/threonine kinase that is activated by falling energy levels and functions to restore cellular energy balance. However, in response to certain cellular stressors, AMPK activation may exacerbate neuronal atrophy and cell death. This review describes the regulation and functions of AMPK, evaluates the controversies in the field, and assesses the potential of targeting AMPK signaling as a neuroprotective treatment for PD.

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“…In particular, we have developed several key techniques, including (i) a sample preparation procedure that eliminates the common e ect of postmortem (PM) degradation of labile metabolites, 26) and (ii) on-tissue derivatization of metabolites that could enhance the analyte ionization e ciency. 27) ese techniques have enabled visualization of diverse metabolite species, including not only abundant phospholipids [28][29][30] but also metabolites present in trace amounts such as minor amino acids, 31) nucleotides, 32,33) neurotransmitters, [34][35][36] and bioactive lipids, 37) in various tissues of diseased model animals (as summarized in Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Development of an Imaging Mass Spectrometry Technique for Visualizing Localized Cellular Signaling Mediators in Tissues

Honda

Suematsu

2015

Mass Spectrometry

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In vivo concentrations of cellular signaling mediators such as in ammatory mediators are normally maintained at very low levels due to their strong ability to induce a biological response. e production, di usion, and decomposition of such mediators are spatio-temporally regulated. erefore, in order to understand biochemical basis of disease progression and develop new therapeutic strategies, it is important to understand the spatiotemporal dynamics of the signaling mediators in vivo, during the progression of disorders, e.g., chronic in ammatory diseases; however, the lack of e ective imaging technology has made it di cult to determine their localizations in vivo. Such characterization requires technical breakthroughs, including molecular imaging methods that are sensitive enough to detect low levels of metabolites in the heterogeneous tissue regions in diseased organs. We and other groups have attempted to ll this technical gap by developing highly sensitive imaging mass spectrometry (IMS) technologies. To date, we have established two key techniques toward this goal, including (i) a sample preparation procedure that has eliminated the problem of the postmortem degradation of labile metabolites, and (ii) on-tissue derivatization of metabolites, which can enhance analyte ionization e ciency. Here, we review recent progress in the development of these technologies as well as how the highly sensitive IMS technique has contributed to increasing understanding of the biochemical basis of disease mechanisms, discovery of new diagnostic markers, and development of new therapies.Please cite this article as: Mass Spectrom (Tokyo) 2015; 4(1): A0040

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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

Cited by 87 publications

References 60 publications

α-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation

α-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation

Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson’s Disease

Development of an Imaging Mass Spectrometry Technique for Visualizing Localized Cellular Signaling Mediators in Tissues

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