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.
abstract: 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.
authors.affiliation: Department of Biomedical Sciences, Parkinson's Disorder Research Laboratory, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa, USA.
authors.forename: Muhammet
authors.initials: M
authors.lastname: Ay
authors.affiliation: Department of Biomedical Sciences, Parkinson's Disorder Research Laboratory, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Biomedical Sciences, Parkinson's Disorder Research Laboratory, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Langley
authors.affiliation: Department of Biomedical Sciences, Parkinson's Disorder Research Laboratory, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa, USA.
authors.forename: Huajun
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Biomedical Sciences, Parkinson's Disorder Research Laboratory, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa, USA.
authors.forename: Vellareddy
authors.initials: V
authors.lastname: Anantharam
authors.affiliation: Department of Biomedical Sciences, Parkinson's Disorder Research Laboratory, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa, USA.
authors.forename: Arthi
authors.initials: A
authors.lastname: Kanthasamy
authors.affiliation: Department of Biomedical Sciences, Parkinson's Disorder Research Laboratory, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa, USA.
authors.forename: Anumantha G
authors.identifier: 0000-0002-6454-4264
authors.initials: AG
authors.lastname: Kanthasamy
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D028361:Mitochondrial Diseases / Q000150:complications / Q000188:drug therapy* / Q000209:etiology* / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000209:etiology*; D016627:Oxidopamine / Q000633:toxicity; D010101:Oxygen Consumption / Q000187:drug effects / Q000235:genetics; D010300:Parkinson Disease / Q000150:complications* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011794:Quercetin / Q000627:therapeutic use*; D050396:TRPP Cation Channels / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D000975:Antioxidants; D004268:DNA-Binding Proteins; D004298:Dopamine; D024101:Mitochondrial Proteins; D016627:Oxidopamine; D011794:Quercetin; D050396:TRPP Cation Channels; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; C422562:mitochondrial transcription factor A
keywords: MitoPark; PGC-1α; PKD1; Parkinson's disease; mitochondrial biogenesis; quercetin