Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 129, Issue -, Pages 73-87Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2018.08.033
Keywords
Dopaminergic neurogenesis; Parkinson's disease; Wnt/beta-catenin signaling; Mitochondrial biogenesis; Apoptosis; ROS
Funding
- Council of Scientific and Industrial Research (CSIR) Network grants miND [BSC0115]
- Indian Council of Medical Research (ICMR), New Delhi India
- CSIR, New Delhi - India
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Wnts and the components of Wnt/beta-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/beta-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/beta-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/beta-catenin signaling in substantia nigra pars compacta (SNpc). We used shRNA lentiviruses to genetically knockdown Axin-2 to up-regulate Wnt/beta-catenin signaling in SNpc in parkinsonian rats. Genetic knockdown of Axin-2 up-regulates Wnt/beta-catenin signaling by destabilizing the beta-catenin degradation complex in SNpc in parkinsonian rats. Axin-2 shRNA mediated activation of Wnt/beta-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/beta-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.
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