Recent Advances on the Role of GSK3β in the Pathogenesis of Amyotrophic Lateral Sclerosis.

Kiyoung Kim,Jang-Won Lee,Hyun-Jun Choi,Hyung-Jun Kim,Sun Joo Cha

doi:10.3390/brainsci10100675

Abstract

Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease characterized by progressive motor neuron degeneration. Although several studies on genes involved in ALS have substantially expanded and improved our understanding of ALS pathogenesis, the exact molecular mechanisms underlying this disease remain poorly understood. Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine-protein kinase that plays a critical role in the regulation of various cellular signaling pathways. Dysregulation of GSK3β activity in neuronal cells has been implicated in the pathogenesis of neurodegenerative diseases. Previous research indicates that GSK3β inactivation plays a neuroprotective role in ALS pathogenesis. GSK3β activity shows an increase in various ALS models and patients. Furthermore, GSK3β inhibition can suppress the defective phenotypes caused by SOD, TDP-43, and FUS expression in various models. This review focuses on the most recent studies related to the therapeutic effect of GSK3β in ALS and provides an overview of how the dysfunction of GSK3β activity contributes to ALS pathogenesis.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective degeneration of the upper and lower motor neurons in the brain and spinal cord [1,2,3]
Data from several studies indicate that protein aggregation, proteasomal dysfunction, mitochondrial defects, neuroinflammation, and oxidative stress are involved in ALS pathogenesis
Understanding cellular signaling pathways, such as Glycogen synthase kinase 3 (GSK3), which regulate neuronal dysfunctions linked to ALS pathogenesis, is important for the development of new strategies for ALS treatment

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective degeneration of the upper and lower motor neurons in the brain and spinal cord [1,2,3]. Recent studies have discovered various genetic susceptibility factors, using several in vivo and in vitro models, that could explain the underlying mechanisms involved in ALS pathogenesis. Understanding these mechanisms would be immensely helpful for developing new drug targets for ALS treatment. Other studies reported a role for GSK3α in central nervous system functioning and possible involvement in the development of psychiatric disorders [15]. Recent studies have suggested a possible role of GSK3β in neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) [16,17]. We present the evidence from these GSK3β studies in ALS and summarize the data into two categories: in vitro and in vivo models

Role of GSK3β Signaling in Neurons

Studies Exploring the Role of GSK3β in In Vivo Models of ALS

Studies Exploring the Role of GSK3β in In Vitro Models of ALS

Inhibitors of GSK3β in ALS Clinical Trials

Discussion

Findings

Conclusions

Key Findings