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Molecular mechanisms underlying protective effects of quercetin against mitochondrial dysfunction and progressive dopaminergic neurodegeneration in cell culture and MitoPark transgenic mouse models of Parkinson's Disease

Journal of neurochemistry, 2017-06, Vol.141 (5), p.766-782 [Peer Reviewed Journal]

2017 International Society for Neurochemistry ;2017 International Society for Neurochemistry. ;Copyright © 2017 International Society for Neurochemistry ;ISSN: 0022-3042 ;EISSN: 1471-4159 ;DOI: 10.1111/jnc.14033 ;PMID: 28376279

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Title:
Molecular mechanisms underlying protective effects of quercetin against mitochondrial dysfunction and progressive dopaminergic neurodegeneration in cell culture and MitoPark transgenic mouse models of Parkinson's Disease
Author: Ay, Muhammet ; Luo, Jie ; Langley, Monica ; Jin, Huajun ; Anantharam, Vellareddy ; Kanthasamy, Arthi ; Kanthasamy, Anumantha G.
Subjects: 6-Hydroxydopamine ; Activation analysis ; Adrenergic Agents - toxicity ; AKT protein ; Animal models ; Animals ; Antioxidants - therapeutic use ; Binding ; Bioenergetics ; Brain ; Brain-derived neurotrophic factor ; Cell activation ; Cell culture ; Cell Line, Transformed ; Cell survival ; Cell Survival - drug effects ; Cell Survival - genetics ; Content analysis ; Cyclic AMP ; DNA-Binding Proteins - genetics ; Dopamine ; Dopamine - metabolism ; Dopamine D1 receptors ; Exploratory Behavior - drug effects ; Female ; Flavonoids ; Gene expression ; Kinases ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitochondria ; mitochondrial biogenesis ; Mitochondrial Diseases - complications ; Mitochondrial Diseases - drug therapy ; Mitochondrial Diseases - etiology ; Mitochondrial Diseases - genetics ; Mitochondrial DNA ; Mitochondrial Proteins - genetics ; MitoPark ; Molecular modelling ; Movement disorders ; Neostriatum ; Nerve Degeneration - drug therapy ; Nerve Degeneration - etiology ; Neurodegeneration ; Neurodegenerative diseases ; Neurotoxicity ; Oxidopamine - toxicity ; Oxygen Consumption - drug effects ; Oxygen Consumption - genetics ; Parkinson Disease - complications ; Parkinson Disease - genetics ; Parkinson's disease ; Parkinsons disease ; PGC‐1α ; Pharmacology ; Phosphorylation ; Phosphorylation - drug effects ; Phosphorylation - genetics ; PKD1 ; Plant diseases ; Plants (botany) ; Polymerase chain reaction ; Protein kinase ; Proteins ; quercetin ; Quercetin - therapeutic use ; Rodents ; Survival ; Transcription Factors - genetics ; Transgenic mice ; TRPP Cation Channels - metabolism ; Tyrosine 3-Monooxygenase - metabolism
Is Part Of: Journal of neurochemistry, 2017-06, Vol.141 (5), p.766-782
Description: Quercetin, one of the major flavonoids in plants, has been recently reported to have neuroprotective effects against neurodegenerative processes. However, since the molecular signaling mechanisms governing these effects are not well clarified, we evaluated quercetin's effect on the neuroprotective signaling events in dopaminergic neuronal models and further tested its efficacy in the MitoPark transgenic mouse model of Parkinson's disease (PD). Western blot analysis revealed that quercetin significantly induced the activation of two major cell survival kinases, protein kinase D1 (PKD1) and Akt in MN9D dopaminergic neuronal cells. Furthermore, pharmacological inhibition or siRNA knockdown of PKD1 blocked the activation of Akt, suggesting that PKD1 acts as an upstream regulator of Akt in quercetin‐mediated neuroprotective signaling. Quercetin also enhanced cAMP response‐element binding protein phosphorylation and expression of the cAMP response‐element binding protein target gene brain‐derived neurotrophic factor. Results from qRT‐PCR, Western blot analysis, mtDNA content analysis, and MitoTracker assay experiments revealed that quercetin augmented mitochondrial biogenesis. Quercetin also increased mitochondrial bioenergetics capacity and protected MN9D cells against 6‐hydroxydopamine‐induced neurotoxicity. To further evaluate the neuroprotective efficacy of quercetin against the mitochondrial dysfunction underlying PD, we used the progressive dopaminergic neurodegenerative MitoPark transgenic mouse model of PD. Oral administration of quercetin significantly reversed behavioral deficits, striatal dopamine depletion, and TH neuronal cell loss in MitoPark mice. Together, our findings demonstrate that quercetin activates the PKD1‐Akt cell survival signaling axis and suggest that further exploration of quercetin as a promising neuroprotective agent for treating PD may offer clinical benefits. We investigated the molecular mechanisms governing the neuroprotective effect of quercetin in a progressive neurodegenerative mouse model of Parkinson's disease (PD). Quercetin treatment activated PKD1 and Akt pro‐survival kinases and enhanced mitochondrial biogenesis by up‐regulating PGC‐1α and TFAM. Collectively, our data suggest that quercetin is a promising neuroprotective agent for treating PD.
Publisher: England: Blackwell Publishing Ltd
Language: English
Identifier: ISSN: 0022-3042
EISSN: 1471-4159
DOI: 10.1111/jnc.14033
PMID: 28376279
Source: IngentaConnect Open Access
Geneva Foundation Free Medical Journals at publisher websites
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Molecular mechanisms underlying protective effects of quercetin against mitochondrial dysfunction and progressive dopaminergic neurodegeneration in cell culture and MitoPark transgenic mouse models of Parkinson's Disease

2017 International Society for Neurochemistry ;2017 International Society for Neurochemistry. ;Copyright © 2017 International Society for Neurochemistry ;ISSN: 0022-3042 ;EISSN: 1471-4159 ;DOI: 10.1111/jnc.14033 ;PMID: 28376279

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