Perturbational Profiling of Metabolites in Patient Fibroblasts Implicates α-Aminoadipate as a Potential Biomarker for Bipolar Disorder

Abstract

Many studies suggest the presence of aberrations in cellular metabolism in bipolar disorder. We studied the metabolome in bipolar disorder to gain insight into cellular pathways that may be dysregulated in bipolar disorder and to discover evidence of novel biomarkers. We measured polar and nonpolar metabolites in fibroblasts from subjects with bipolar I disorder and matched healthy control subjects, under normal conditions and with two physiologic perturbations: low-glucose media and exposure to the stress-mediating hormone dexamethasone. Metabolites that were significantly different between bipolar and control subjects showed distinct separation by principal components analysis methods. The most statistically significant findings were observed in the perturbation experiments. The metabolite with the lowest p value in both the low-glucose and dexamethasone experiments was α-aminoadipate, whose intracellular level was consistently lower in bipolar subjects. Our study implicates α-aminoadipate as a possible biomarker in bipolar disorder that manifests under cellular stress. This is an intriguing finding given the known role of α-aminoadipate in the modulation of kynurenic acid in the brain, especially as abnormal kynurenic acid levels have been implicated in bipolar disorder.

Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder

“…There is a growing recognition of important roles for non-coding RNA in psychiatric disorders, including bipolar disorder, though the exact nature of these roles has yet to be delineated [76,77]. Previous studies with neuroimaging, postmortem brains, and patient-derived cells that have explored the disease biology of BPI have led to results indicating deficits in different neural circuits, reduced glial populations in the prefrontal cortex, differences in the metabolic pathways in the presence of stress, and abnormalities in neuronal and calcium signaling [14,15,[78][79][80][81]. When evaluating results from neuroimaging studies, postmortem tissue, and investigation of primary cells, it is often difficult to delineate the contribution of genetic factors from confounding effects due to medications, nonprescription drugs, stress, environmental effects, or downstream effects of the disease process.…”

“…We also note that our experiments do not take into account environmental factors that may impinge on the genetic background resulting in disease onset. There are possible ways to use specific perturbations in in vitro cell culture models to simulate gene-environment interactions to reveal cellular pathways relevant to disease biology [80,88]. The new possibilities of generating ex vivo two-dimensional and three-dimensional cellular models from patient-derived iPSCs provide a valuable method for interrogating the disease biology of neuropsychiatric disorders and to identify cellular processes and molecular targets that can be targeted for therapeutic applications.…”

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

“…In fibroblasts from patients with BD, increased cyclic AMP response element‐binding protein signaling, decreased α‐aminoadipic acid, and decreased phosphorylated extracellular‐signal‐regulated kinase have been reported. In fibroblasts of BD patients, mitochondrial shape was altered .…”

HDAC6 Modulates Signaling Pathways Relevant to Synaptic Biology and Neuronal Differentiation in Human Stem Cell-Derived Neurons

“…When heterozygous conditional loss-of-function NRXN1 mutations were introduced into human embryonic stem cells (ESCs), it resulted in severe deficits in stimulus-dependent transmitter release but similar experiments in mice with Nrxn1α mutations did not show this impairment [62]. These considerations have led to a note of caution about focusing exclusively on tissue from animal studies for preclinical investigations and have led to the development of different approaches to study the biology of disease and therapeutics in cells from human subjects [63,64,65,66,67].…”