Mechanisms and Therapeutic Implications of GSK-3 in Treating Neurodegeneration

Abstract

Neurodegenerative disorders are spreading worldwide and are one of the greatest threats to public health. There is currently no adequate therapy for these disorders, and therefore there is an urgent need to accelerate the discovery and development of effective treatments. Although neurodegenerative disorders are broad ranging and highly complex, they may share overlapping mechanisms, and thus potentially manifest common targets for therapeutic interventions. Glycogen synthase kinase-3 (GSK-3) is now acknowledged to be a central player in regulating mood behavior, cognitive functions, and neuron viability. Indeed, many targets controlled by GSK-3 are critically involved in progressing neuron deterioration and disease pathogenesis. In this review, we focus on three pathways that represent prominent mechanisms linking GSK-3 with neurodegenerative disorders: cytoskeleton organization, the mammalian target of rapamycin (mTOR)/autophagy axis, and mitochondria. We also consider the challenges and opportunities in the development of GSK-3 inhibitors for treating neurodegeneration.

Keywords: GSK-3; GSK-3 inhibitors; autophagy; lysosome; mTOR; microtubules; mitochondria; neurodegeneration.

Figure 1

GSK-3 regulatory pathways in neurons. GSK-3 regulates microtubule (MT) stability and dynamics. Phosphorylation of MT binding proteins (MAPs) by GSK-3 reduces their binding to MT, and GSK-3 phosphorylation of kinesin 1 impairs anterograde and retrograde transport. GSK-3 activation of mTORC1 inhibits autophagic and lysosomal activity. GSK3 regulates mitochondrial energy metabolism and mitochondria-mediated cell death. GSK-3 destabilizes peroxisome proliferator-activated receptor γ, PGC1α, and inhibits its transcriptional activity, phosphorylation of dynamin-related protein1, DRP1, by GSK3 enhances mitochondria fission, and phosphorylation of Voltage-dependent anion-selective channel 1, VADC1, and bcl-2 associated proteins, Bax, by GSK-3 enhances their induced-apoptotic activity. Finally, GSK-3 impairs mitochondria and ER communication by disrupting proteins associated with the microdomain, mitochondria-associated membranes, MAM.

Figure 2

GSK-3 SCIs. (a) GSK-3 substrate binding sites are highlighted. Blue, the phosphate binding pocket; orange, the 89-95 loop; beige, the hydrophobic patch (Ile, 213, Val 214, Tyr 216). (b) Types of substrate competitive inhibitors (SCIs): the primed substrate is phosphorylated by GSK-3 and upon phosphorylation dissociates from the enzyme, the pseudosubstrate SCI is a mutated substrate that cannot be phosphorylated by the kinase, the “substrate converted into an inhibitor” is a substrate that upon phosphorylation remains bound to the kinase.