Systems Biology Understanding of the Effects of Lithium on Affective and Neurodegenerative Disorders.

Weihao Ge,Eric Jakobsson

doi:10.3389/fnins.2018.00933

Abstract

Lithium has many widely varying biochemical and phenomenological effects, suggesting that a systems biology approach is required to understand its action. Multiple lines of evidence point to lithium intake and consequent blood levels as important determinants of incidence of neurodegenerative disease, showing that understanding lithium action is of high importance. In this paper we undertake first steps toward a systems approach by analyzing mutual enrichment between the interactomes of lithium-sensitive enzymes and the pathways associated with affective and neurodegenerative disorders. This work integrates information from two important databases, STRING and KEGG pathways. We find that for the majority of neurodegenerative disorders the mutual enrichment is many times greater than chance, reinforcing previous lines of evidence that lithium is an important influence on incidence of neurodegeneration. Our work suggests rational prioritization for which disorders are likely to be most sensitive to lithium and identifies genes that are likely to be useful targets for therapy adjunct to lithium.

Highlights

Lithium is typically a first line therapy for bipolar disorder, including associated depression as well as mania (Post, 2016)
We hope that the results described in this paper and more detailed Supplementary Material will contribute to prioritizing and designing clinical trials of lithium for neural disease
To provide context for such prioritization and design, it is essential to take into account the ways in which lithium is unique, both as a pharmaceutical and as an ion that is ubiquitous in the environment, and ubiquitous in the water and food we ingest (Jakobsson et al, 2017): 1. Unlike other ions, lithium is not regulated by selective membrane transport processes

Summary

Introduction

Lithium is typically a first line therapy for bipolar disorder, including associated depression as well as mania (Post, 2016). Much of lithium’s biochemical action may be summarized by noting that it inhibits enzymes that have magnesium as a co-factor (Jakobsson et al, 2017). One such enzyme, the lithium-sensitive enzyme glycogen synthase kinase 3-beta (GSK3B) (Freland and Beaulieu, 2012) inhibits signaling induced by Brain-Derived Neurotrophic Factor (BDNF) (Mai et al, 2002). BDNF may be a key bridge between affective and neurodegenerative disorders, since levels of this enzyme have been implicated in depression (Karege et al, 2002), bipolar disorder(Cunha et al, 2006; Post, 2007), and dementia (Weinstein et al, 2014).

Methods

Results

Conclusion