1. Academic Validation
  2. Inhibition of Wnt/β-catenin signaling attenuates axonal degeneration in models of Parkinson's disease

Inhibition of Wnt/β-catenin signaling attenuates axonal degeneration in models of Parkinson's disease

  • Neurochem Int. 2022 Oct;159:105389. doi: 10.1016/j.neuint.2022.105389.
Yan-Lin Huang 1 Jian-Nan Zhang 2 Tian-Zhong Hou 1 Li Gu 1 Hui-Min Yang 1 Hong Zhang 3
Affiliations

Affiliations

  • 1 Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, 100069, China.
  • 2 Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, 100069, China. Electronic address: jnzhang86@ccmu.edu.cn.
  • 3 Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, 100069, China. Electronic address: hzhang@ccmu.edu.cn.
Abstract

There are currently no treatments to delay or prevent Parkinson's disease (PD), and protective treatments require early administration. Targeting axonal degeneration in early PD could have an important clinical effect; however, the underlying molecular mechanisms controlling axonal degeneration in PD are not fully understood. Here, we studied the role of Wnt/β-catenin signaling in axonal degeneration induced by 6-hydroxydopamine (6-OHDA) or overexpression of alpha-synuclein (α-Syn) in vitro and in vivo. We found that the levels of both β-catenin and p-S9-glycogen synthase kinase-3β (GSK-3β) increased and the levels of phosphorylated β-catenin (p-β-catenin) decreased during 6-OHDA-induced axonal degeneration and that the inhibitors of the Wnt/β-catenin pathway IWR-1 and Dickkopf-1 (DKK-1) attenuated the degenerative process in primary neurons in vitro. Furthermore, IWR-1 enhanced the increase of LC3-II levels and the decrease of p62 triggered by 6-OHDA treatment, whereas the Autophagy Inhibitor 3-Methyladenine (3-MA) alleviated the protective effect of IWR-1 on axons in vitro. Consistent with the in vitro findings, both β-catenin and p-S9-GSK-3β were upregulated in a 6-OHDA-induced rat PD model, and blocking the Wnt/β-catenin pathway with DKK-1 attenuated the degeneration of dopaminergic axons at an early time point in vivo. The protective effect of inhibition of Wnt/β-catenin signaling was further confirmed in an α-Syn overexpression-induced animal models of PD. Taken together, these data indicate that the Wnt/β-catenin pathway is involved axonal degeneration in PD, and suggest that Wnt/β-catenin pathway inhibitors have the therapeutic potential for the prevention of PD.

Keywords

6-Hydroxydopamine; Alpha-synuclein; Autophagy; Axonal degeneration; Parkinson's disease; Wnt.

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