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

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.

Dysregulated biodynamics in metabolic attractor systems precede the emergence of amyotrophic lateral sclerosis

“…Supporting this, both linear and tree-based classification algorithms that were used for the predictive analysis identified these elements as the most important contributors to predictive performance; and, follow-up analyses which utilized only features derived from these elements yielded good performance. Our data are in agreement with clinical and experimental studies revealing copper dyshomeostasis in ALS [30], and add to the growing literature relating lithium regulation to ALS [31,32].…”

Lithium ions display weak interaction with amyloid-beta (Aβ) peptides and have minor effects on their aggregation

“…Lithium salts are commonly used in psychiatric medication, even though it is not understood how the Li + ions affect the molecular mechanisms underlying the psychiatric disorders (Dell'Osso et al, 2016). Unlike other pharmaceuticals, Li + is widely non-selective in its biochemical effects, possibly due to its general propen-sity to inhibit the many enzymes that have magnesium as a cofactor (Ge & Jakobsson, 2018).…”

Systems Biology Understanding of the Effects of Lithium on Cancer

“…By far the most common medical use of lithium is as a first line therapy for bipolar disorder, including associated depression as well as mania (1). A comprehensive review of the literature confirms that lithium is also effective against unipolar depression with unique anti-suicidal effectiveness, and may also be useful against cancer and neurodegenerative disease (2, 3).…”