Abstract
Wnts and the components of Wnt/β-catenin signaling are widely expressed in midbrain and required to control the fate specification of dopaminergic (DAergic) neurons, a neuronal population that specifically degenerate in Parkinson's disease (PD). Accumulating evidence suggest that mitochondrial dysfunction plays a key role in pathogenesis of PD. Axin-2, a negative regulator of Wnt/β-catenin signaling affects mitochondrial biogenesis and death/birth of new DAergic neurons is not fully explored. We investigated the functional role of Axin-2/Wnt/β-catenin signaling in mitochondrial biogenesis and DAergic neurogenesis in 6-hydroxydopamine (6-OHDA) induced rat model of PD-like phenotypes. We demonstrate that single unilateral injection of 6-OHDA into the medial forebrain bundle (MFB) potentially dysregulates Wnt/β-catenin signaling in substantia nigra pars compacta (SNpc). We used shRNA lentiviruses to genetically knockdown Axin-2 to up-regulate Wnt/β-catenin signaling in SNpc in parkinsonian rats. Genetic knockdown of Axin-2 up-regulates Wnt/β-catenin signaling by destabilizing the β-catenin degradation complex in SNpc in parkinsonian rats. Axin-2 shRNA mediated activation of Wnt/β-catenin signaling improved behavioural functions and protected the nigral DAergic neurons by increasing mitochondrial functionality in parkinsonian rats. Axin-2 shRNA treatment reduced apoptotic signaling, autophagy and ROS generation and improved mitochondrial membrane potential which promotes mitochondrial biogenesis in SNpc in parkinsonian rats. Interestingly, Axin-2 shRNA-mediated up-regulation of Wnt/β-catenin signaling enhanced net DAergic neurogenesis by regulating proneural genes (Nurr-1, Pitx-3, Ngn-2, and NeuroD1) and mitochondrial biogenesis in SNpc in parkinsonian rats. Therefore, our data suggest that pharmacological/genetic manipulation of Wnt signaling that enhances the endogenous regenerative capacity of DAergic neurons may have implication for regenerative approaches in PD.
Keywords:
Apoptosis; Dopaminergic neurogenesis; Mitochondrial biogenesis; Parkinson's disease; ROS; Wnt/β-catenin signaling.
Copyright © 2018 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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Dopaminergic Neurons / drug effects
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Dopaminergic Neurons / metabolism*
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Dopaminergic Neurons / pathology
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Gene Expression Regulation
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Injections, Intraventricular
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Male
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Medial Forebrain Bundle / drug effects
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Medial Forebrain Bundle / metabolism
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Medial Forebrain Bundle / pathology
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Mesencephalon / drug effects
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Mesencephalon / metabolism
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Mesencephalon / pathology
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Mitochondria / genetics
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Mitochondria / metabolism
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neurogenesis / genetics*
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Nuclear Receptor Subfamily 4, Group A, Member 2 / genetics
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Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism
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Organelle Biogenesis
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Oxidopamine / administration & dosage
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Parkinson Disease, Secondary / chemically induced
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Parkinson Disease, Secondary / genetics*
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Parkinson Disease, Secondary / metabolism
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Parkinson Disease, Secondary / pathology
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Pars Compacta / drug effects
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Pars Compacta / metabolism
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Pars Compacta / pathology
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Rats
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Rats, Sprague-Dawley
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Stereotaxic Techniques
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Wnt Proteins / genetics*
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Wnt Proteins / metabolism
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Wnt Signaling Pathway*
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beta Catenin / genetics*
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beta Catenin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Axin2 protein, rat
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Basic Helix-Loop-Helix Transcription Factors
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Carrier Proteins
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Ctnnb1 protein, rat
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Homeodomain Proteins
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Nerve Tissue Proteins
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Neurod1 protein, rat
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Neurog2 protein, rat
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Nr4a2 protein, rat
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Nuclear Receptor Subfamily 4, Group A, Member 2
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RNA, Small Interfering
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Transcription Factors
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Wnt Proteins
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beta Catenin
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homeobox protein PITX3
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Oxidopamine