Dataset Information

Loneliness 5 years ante-mortem is associated with disease-related differential gene expression in postmortem dorsolateral prefrontal cortex.

ABSTRACT: Subjective social isolation, loneliness, is associated with poor mental and physical health, but the underlying molecular mechanisms are poorly understood. Here we analyzed loneliness data collected on average 5 years ante-mortem and RNA gene expression at death in postmortem dorsolateral prefrontal cortex (DLPFC) from 181 participants in the Rush Memory and Aging Project (MAP), a longitudinal, prospective cohort study of common chronic conditions of aging. Our analytic protocol controlled for biographical variables (age, sex, education), psychological and health variables (depressive symptoms, interval between assessment and autopsy, slope of cognitive decline, AD pathology, presence of infarcts) and RNA integrity. Our results are based on a pre-ranked Gene Set Enrichment Analysis (GSEA) at FDR-corrected q-values <0.05, using these collections from the Molecular Signatures Database (v6.0 MSigDB): (1) Hallmarks, (2) Canonical, (3) Gene Ontology (GO), (4) Chemical and Genetic Perturbations, (5) Immunologic Signatures, (6) Oncogenic Signatures, and (7) Cancer Modules. We now report on 337 up-regulated and 43 down-regulated gene sets, among which the most significant ones were associated with Alzheimer's disease, psychiatric illness, immune dysfunction, and cancer. These gene sets constitute attractive targets for future studies into the molecular mechanisms by which loneliness exacerbates a wide range of neurodegenerative, psychiatric, and somatic illnesses.

SUBMITTER: Canli T

PROVIDER: S-EPMC5802527 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Loneliness 5 years ante-mortem is associated with disease-related differential gene expression in postmortem dorsolateral prefrontal cortex.

Canli Turhan T Yu Lei L Yu Xiaoqing X Zhao Hongyu H Fleischman Debra D Wilson Robert S RS De Jager Philip L PL Bennett David A DA

Translational psychiatry 20180110 1

Subjective social isolation, loneliness, is associated with poor mental and physical health, but the underlying molecular mechanisms are poorly understood. Here we analyzed loneliness data collected on average 5 years ante-mortem and RNA gene expression at death in postmortem dorsolateral prefrontal cortex (DLPFC) from 181 participants in the Rush Memory and Aging Project (MAP), a longitudinal, prospective cohort study of common chronic conditions of aging. Our analytic protocol controlled for b ...[more]

PMID: 29317593

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Project description:The pathophysiology of schizophrenia includes altered neurotransmission, dysregulated intracellular signaling pathway activity, and abnormal dendritic morphology that contribute to deficits of synaptic plasticity in the disorder. These processes all require dynamic protein-protein interactions at cell membranes. Lipid modifications target proteins to membranes by increasing substrate hydrophobicity by the addition of a fatty acid or isoprenyl moiety, and recent evidence suggests that dysregulated posttranslational lipid modifications may play a role in multiple neuropsychiatric disorders, including schizophrenia. Consistent with these emerging findings, we have recently reported decreased protein S-palmitoylation in schizophrenia. Protein prenylation is a lipid modification that occurs upstream of S-palmitoylation on many protein substrates, facilitating membrane localization and activity of key intracellular signaling proteins. Accordingly, we hypothesized that, in addition to palmitoylation, protein prenylation may be abnormal in schizophrenia. To test this, we assayed protein expression of the five prenyltransferase subunits (FNTA, FNTB, PGGT1B, RABGGTA, and RABGGTB) in postmortem dorsolateral prefrontal cortex from patients with schizophrenia and paired comparison subjects (n = 13 pairs). We found decreased levels of FNTA (14%), PGGT1B (13%), and RABGGTB (8%) in schizophrenia. To determine whether upstream or downstream factors may be driving these changes, we also assayed protein expression of the isoprenoid synthases FDPS and GGPS1 and prenylation-dependent processing enzymes RCE and ICMT. We found these upstream and downstream enzymes to have normal protein expression. To rule out effects from chronic antipsychotic treatment, we assayed FNTA, PGGT1B, and RABGGTB in the cortex from rats treated long-term with haloperidol decanoate and found no change in the expression of these proteins. Given the role prenylation plays in localization of key signaling proteins found at the synapse, these data offer a potential mechanism underlying abnormal protein-protein interactions and protein localization in schizophrenia.

Dataset Information

Loneliness 5 years ante-mortem is associated with disease-related differential gene expression in postmortem dorsolateral prefrontal cortex.

Publications

Loneliness 5 years ante-mortem is associated with disease-related differential gene expression in postmortem dorsolateral prefrontal cortex.

Similar Datasets

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