Targeting the Wnt/β-catenin pathway in neurodegenerative diseases: recent approaches and current challenges

ABSTRACT

Introduction

Wnt/β-catenin signaling is an evolutionarily conserved pathway having a crucial role in embryonic and adult life. Specifically, the Wnt/β-catenin axis is pivotal to the development and homeostasis of the nervous system, and its dysregulation has been associated with various neurological disorders, including neurodegenerative diseases. Therefore, this signaling pathway has been proposed as a potential therapeutic target against neurodegeneration.

Areas covered

This review focuses on the role of Wnt/β-catenin pathway in the pathogenesis of neurodegenerative diseases, including Parkinson’s, Alzheimer’s Diseases and Amyotrophic Lateral Sclerosis. The evidence showing that defects in the signaling might be involved in the development of these diseases, and the pharmacological approaches tested so far, are discussed. The possibilities that this pathway offers in terms of new therapeutic opportunities are also considered.

Expert opinion

The increasing interest paid to the role of Wnt/β-catenin pathway in the onset of neurodegenerative diseases demonstrates how targeting this signaling for therapeutic purposes could be a great opportunity for both neuroprotection and neurorepair. Without overlooking some licit concerns about drug safety and delivery to the brain, there is growing and more convincing evidence that restoring this signaling in neurodegenerative diseases may strongly increase the chance to develop disease-modifying treatments for these brain pathologies.

KEYWORDS:

• Wnt/β-catenin pathway
• neurodegenerative diseases
• molecules targeting Wnt signaling
• Parkinson’s disease
• Alzheimer’s disease
• amyotrophic lateral sclerosis

Article highlights

• Restoring the Wnt/β-catenin signaling in neurodegenerative diseases may strongly increase the chance of improving the current therapeutic strategies, towards the development of innovative disease-modifying treatments.

• The knowledge on the molecular mechanisms driving the Wnt/β-catenin pathway and its role in the onset and progression of neurodegenerative diseases are increasing, and many compounds targeting this signaling have been tested as neuroprotective or neuroreparative agents.

• Among the bioactive modulators of the Wnt/β-catenin signaling, that are under preclinical investigation as possible therapeutics for PD and AD, there are drugs targeting molecules participating at upstream events of the signaling and some nature-derived compounds that seem to promote neuronal differentiation and to possess neuroprotective ability.

• The currently available therapies for neurodegenerative diseases, and in particular for PD and AD, are mainly symptomatic and not curative.

• Based on all the literature data, the restoration of Wnt/β-catenin signaling in the brain of patients suffering from neurodegenerative diseases, and in particular PD and AD, would enhance most of the neuronal functions that are impaired in these pathologies.

• The goal of the therapeutic application of Wnt activators/modulators in patients suffering from neurodegenerative diseases should be to restore rather than to over-stimulate, the Wnt/β-catenin signaling, thus re-establishing the balancing between Wnt-OFF state and Wnt-ON state.

This box summarizes key points contained in the article.

Acknowledgments

M Paggiolu and P Papa of the IFT-CNR are thanked for their scientific secretariat support and administrative support, respectively.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work is supported by the Institute of Translational Pharmacology (IFT), the National Research Council of Italy (CNR), Project DSB.AD007.088 (to A Serafino), and by ARISLA (Project SPLICEALS), CNR Flagship Project INTEROMICS – PROALS) and by the Ministry of Education, Universities and Research (MIUR) Project PRIN-2015LFPNMN (to M Cozzolino).