Axin-2 Knockdown Promote Mitochondrial Biogenesis and Dopaminergic Neurogenesis by regulating Wnt/β-catenin Signaling in Rat Model of Parkinson's disease Akanksha Mishra1,2,Sonu Singh1, Shubha Shukla1,2 1Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow (U.P.), India; 2Academy of Scientific and Innovative Research, New Delhi, India email id: firstname.lastname@example.org
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, but whether Wnt/β-catenin signaling affects the mitochondrial biogenesis and death/birth of new DAergic neurons is not fully explored. We investigated the functional role of Wnt/β-catenin signaling in mitochondrial biogenesis, apoptosis 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 medial forebrain bundle potentially dysregulate Wnt/β-catenin signaling in 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 behavioral functions and protected the nigral DAergic neurons by increasing mitochondrial functionality in parkinsonian rats. Axin-2 shRNA treatment reduced apoptotic signaling (extrinsic and intrinsic pathways), mitochondrial and cellular ROS level and improved mitochondrial membrane potential that lead to improved mirochondrial 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 mitochondrial dynamics in SNpc in parkinsonian rats. Therefore, our data suggest that pharmacological/genetic manipulation that enhances endogenous regenerative capacity of DAergic neurons may have implication for regenerative approaches in PD. Keywords:Dopaminergic neurogenesis; Parkinson's disease; Wnt/β-catenin signaling; Mitochondrial biogenesis; Apoptosis; ROS
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