The GSK3-NRF2 Axis in Suicide

Mutations in the genes coding for tryptophan-hydrolase-2 and the scaffold protein FKBP5 are associated with an increased risk of suicide. The mutation in both cases enhances the enzymatic activity of glycogen synthase kinase-3 (GSK3). Conversely, anti-suicidal medications, such as lithium, clozapine...

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Published inPsychiatry international (Basel) Vol. 2; no. 1; pp. 108 - 119
Main Author Kalkman, Hans O.
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 01.03.2021
Subjects
Antibiotics
Bipolar disorder
Brain-derived neurotrophic factor
Cytokines
Genes
GSK3
ketamine
Kinases
Lymphoma
Mental depression
minocycline
Mutation
nicotinic-α7 receptor
NRF2
Phosphatase
Phosphorylation
Proteins
Schizophrenia
suicide pathophysiology
Suicides & suicide attempts
Transcription factors
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Summary:Mutations in the genes coding for tryptophan-hydrolase-2 and the scaffold protein FKBP5 are associated with an increased risk of suicide. The mutation in both cases enhances the enzymatic activity of glycogen synthase kinase-3 (GSK3). Conversely, anti-suicidal medications, such as lithium, clozapine, and ketamine, indirectly inhibit the activity of GSK3. When GSK3 is active, it promotes the metabolic removal of the transcription factor NRF2 (nuclear factor erythroid 2-related factor-2), which suppresses the transcription of multiple genes that encode anti-oxidative and anti-inflammatory proteins. Notably, several suicide-biomarkers bear witness to an ongoing inflammatory process. Moreover, alterations in serum lipid levels measured in suicidal individuals are mirrored by data obtained in mice with genetic deletion of the NRF2 gene. Inflammation is presumably causally related to both dysphoria and anger, two factors relevant for suicide ideation and attempt. Preventing the catabolism of NRF2 could be a strategy to obtain novel suicide-prophylactic medications. Possible candidates are minocycline and nicotinic-α7 agonists. The antibiotic minocycline indirectly activates NRF2-transcriptional activity, whereas the activation of nicotinic-α7 receptors indirectly inhibits GSK3.
ISSN:2673-5318
2673-5318
DOI:10.3390/psychiatryint2010008