HIF-1α/microRNA-128-3p axis protects hippocampal neurons from apoptosis via the <i>Axin1</i>-mediated Wnt/β-catenin signaling pathway in Parkinson’s disease models

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder. A common and disabling disease of the elderly, the standard dopamine replacement therapies do not arrest the ongoing neurodegeneration, thus calling for new treatment strategies. The present study aimed to clarify the functional relevance of the hypoxia inducible factor-1α (HIF-1α)/microRNA-128-3p (miR-128-3p) axis in hippocampal neurodegeneration in a PD mouse model obtained by intraperitoneal injection of MPTP. Targeting relationship between miR-128-3p and <i>Axin1</i> was verified, so we probed the roles of <i>Hif1a</i>, miR-128-3p, and <i>Axin1</i> in apoptosis of hippocampal neurons with gain- and loss-of function experiments using flow cytometry and TUNEL staining. We found that <i>Axin1</i> was upregulated in hippocampal tissues and cells of the MPTP-lesioned mouse model of PD, while <i>Hif1a</i> and miR-128-3p were downregulated. Elevation of HIF-1α/miR-128-3p inhibited apoptosis of hippocampal neurons via Wnt/β-catenin signaling pathway activation due to the suppression of <i>Axin1</i> in PD. In addition, forced overexpression of <i>Hif1a</i> could ameliorate motor dysfunction and pathological changes in the model. Collectively, activation of the HIF-1α/miR-128-3p axis could repress hippocampal neurodegeneration in MPTP-lesioned mice through an activated Wnt/β-catenin pathway due to <i>Axin1</i> downregulation.