HIF-1α/microRNA-128-3p axis protects hippocampal neurons from apoptosis via the Axin1-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 Axin1 was verified, so we probed the roles of Hif1a, miR-128-3p, and Axin1 in apoptosis of hippocampal neurons with gain-and loss-of function experiments using flow cytometry and TUNEL staining. We found that Axin1 was upregulated in hippocampal tissues and cells of the MPTP-lesioned mouse model of PD, while Hif1a 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 Axin1 in PD. In addition, forced overexpression of Hif1a 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 Axin1 downregulation.

MiR-128-3p Alleviates Spinal Cord Ischemia/Reperfusion Injury Associated Neuroinflammation and Cellular Apoptosis via SP1 Suppression in Rat

“…For example, Krichevsky et al (2006) suggested that miR-128-3p is upregulated in the development of the central nervous system. Additionally, high miR-128-3p amounts in neurons alleviate motor deficits in a mouse model of PD ( Tan et al, 2013 ), and it was recently confirmed that miR-128-3p overexpression in the 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP)-injured mouse model of PD reduced hippocampal neuron apoptosis ( Zhang et al, 2020 ). Meanwhile, miR-128-3p protected neurons from apoptosis at the early stage of cerebral ischemia ( Mao et al, 2017 ).…”

“…Meanwhile, synthetic miRNA mimics and anti-miRNA oligonucleotides powerfully mitigate neuroinflammation and neuroapoptosis, and elevate neurological functional recovery in rat models ( He et al, 2015 ; Li et al, 2015 ; Liu et al, 2017 ; Li et al, 2018 ). Recently, miR-128-3p, which is best known as a tumor suppressor ( Huang et al, 2015 ; Zhao et al, 2018 ), has been found to contribute to central nervous system disorders such as PD ( Zhang et al, 2020 ) and glioma ( Huo et al, 2019 ). Mao et al (2017) demonstrated miR-128-3p prevented neuron apoptosis by regulating p38α in the initial stage of brain I/R.…”

T Cell Factor 4 Is Involved in Papillary Thyroid Carcinoma via Regulating Long Non-Coding RNA HCP5

“… 34 Elevation of miR-128-3p inhibits apoptosis and activates Wnt/β-catenin signaling by targeting Axin1 in Parkinson’s disease. 35 Nevertheless, overexpression of miR-128-3p suppresses proliferation, migration, invasion, and inhibit Wnt signaling by targeting NEK2 in breast cancer. 36 Considering these findings, the potential role of TCF4/HCP5/miR-128-3p axis and the hypothesis need to be proved in PTC cells in the future.…”

MicroRNA Dysregulation in Parkinson’s Disease: A Narrative Review

“…MiR-128 protects DA neurons from apoptosis and up-regulates the expression of Excitatory Amino Acid Transporter 4 (EAAT4) by binding to the axis inhibition protein 1 (AXIN1) (Zhou et al, 2018). Further study reported that the increased HIF-1α/miR-128-3p inhibited apoptosis of hippocampal neurons through Wnt/β-catenin signaling pathway activation via the suppression of AXIN1 (Zhang G. et al, 2020).…”

“…The expression of miR-128 decreased in the MPTP-induced PD mice (Zhou et al, 2018;Zhang G. et al, 2020). MiR-128 protects DA neurons from apoptosis and up-regulates the expression of Excitatory Amino Acid Transporter 4 (EAAT4) by binding to the axis inhibition protein 1 (AXIN1) (Zhou et al, 2018).…”