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Cell- and region-specific expression of depression-related protein p11 (S100a10) in the brain.

ABSTRACT: P11 (S100a10), a member of the S100 family of proteins, has widespread distribution in the vertebrate body, including in the brain, where it has a key role in membrane trafficking, vesicle secretion, and endocytosis. Recently, our laboratory has shown that a constitutive knockout of p11 (p11-KO) in mice results in a depressive-like phenotype. Furthermore, p11 has been implicated in major depressive disorder (MDD) and in the actions of antidepressants. Since depression affects multiple brain regions, and the role of p11 has only been determined in a few of these areas, a detailed analysis of p11 expression in the brain is warranted. Here we demonstrate that, although widespread in the brain, p11 expression is restricted to distinct regions, and specific neuronal and nonneuronal cell types. Furthermore, we provide comprehensive mapping of p11 expression using in situ hybridization, immunocytochemistry, and whole-tissue volume imaging. Overall, expression spans multiple brain regions, structures, and cell types, suggesting a complex role of p11 in depression. J. Comp. Neurol. 525:955-975, 2017. © 2016 Wiley Periodicals, Inc.

SUBMITTER: Milosevic A

PROVIDER: S-EPMC5222728 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Cell- and region-specific expression of depression-related protein p11 (S100a10) in the brain.

Milosevic Ana A Liebmann Thomas T Knudsen Margarete M Schintu Nicoletta N Svenningsson Per P Greengard Paul P

The Journal of comparative neurology 20161021 4

P11 (S100a10), a member of the S100 family of proteins, has widespread distribution in the vertebrate body, including in the brain, where it has a key role in membrane trafficking, vesicle secretion, and endocytosis. Recently, our laboratory has shown that a constitutive knockout of p11 (p11-KO) in mice results in a depressive-like phenotype. Furthermore, p11 has been implicated in major depressive disorder (MDD) and in the actions of antidepressants. Since depression affects multiple brain regi ...[more]

PMID: 27616678

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Project description:UnlabelledBackgroundMitochondrial dysfunction (MtD) has been observed in approximately five percent of children with autism spectrum disorders (ASD). MtD could impair highly energy-dependent processes such as neurodevelopment, thereby contributing to autism. Most of the previous studies of MtD in autism have been restricted to the biomarkers of energy metabolism, while most of the genetic studies have been based on mutations in the mitochondrial DNA (mtDNA). Despite the mtDNA, most of the proteins essential for mitochondrial replication and function are encoded by the genomic DNA; so far, there have been very few studies of those genes. Therefore, we carried out a detailed study involving gene expression and genetic association studies of genes related to diverse mitochondrial functions.MethodsFor gene expression analysis, postmortem brain tissues (anterior cingulate gyrus (ACG), motor cortex (MC) and thalamus (THL)) from autism patients (n=8) and controls (n=10) were obtained from the Autism Tissue Program (Princeton, NJ, USA). Quantitative real-time PCR arrays were used to quantify the expression of 84 genes related to diverse functions of mitochondria, including biogenesis, transport, translocation and apoptosis. We used the delta delta Ct (∆∆Ct) method for quantification of gene expression. DNA samples from 841 Caucasian and 188 Japanese families were used in the association study of genes selected from the gene expression analysis. FBAT was used to examine genetic association with autism.ResultsSeveral genes showed brain region-specific expression alterations in autism patients compared to controls. Metaxin 2 (MTX2), neurofilament, light polypeptide (NEFL) and solute carrier family 25, member 27 (SLC25A27) showed consistently reduced expression in the ACG, MC and THL of autism patients. NEFL (P = 0.038; Z-score 2.066) and SLC25A27 (P = 0.046; Z-score 1.990) showed genetic association with autism in Caucasian and Japanese samples, respectively. The expression of DNAJC19, DNM1L, LRPPRC, SLC25A12, SLC25A14, SLC25A24 and TOMM20 were reduced in at least two of the brain regions of autism patients.ConclusionsOur study, though preliminary, brings to light some new genes associated with MtD in autism. If MtD is detected in early stages, treatment strategies aimed at reducing its impact may be adopted.

Project description:Studies in post-mortem human brain tissue have associated major depressive disorder (MDD) with cortical transcriptomic changes, whose potential in vivo impact remains unexplored. To address this translational gap, we recently developed a transcriptome-based polygenic risk score (T-PRS) based on common functional variants capturing 'depression-like' shifts in cortical gene expression. Here, we used a non-clinical sample of young adults (n = 482, Duke Neurogenetics Study: 53% women; aged 19.8 ± 1.2 years) to map T-PRS onto brain morphology measures, including Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index, as well as broad MDD risk, indexed by self-reported family history of depression. We conducted side-by-side comparisons with a PRS independently derived from a Psychiatric Genomics Consortium (PGC) MDD GWAS (PGC-PRS), and sought to link T-PRS with diagnosis and symptom severity directly in PGC-MDD participants (n = 29,340, 59% women; 12,923 MDD cases, 16,417 controls). T-PRS was associated with smaller amygdala volume in women (t = -3.478, p = 0.001) and lower prefrontal gyrification across sexes. In men, T-PRS was associated with hypergyrification in temporal and occipital regions. Prefrontal hypogyrification mediated a male-specific indirect link between T-PRS and familial depression (b = 0.005, p = 0.029). PGC-PRS was similarly associated with lower amygdala volume and cortical gyrification; however, both effects were male-specific and hypogyrification emerged in distinct parietal and temporo-occipital regions, unassociated with familial depression. In PGC-MDD, T-PRS did not predict diagnosis (OR = 1.007, 95% CI = [0.997-1.018]) but correlated with symptom severity in men (rho = 0.175, p = 7.957 × 10-4) in one cohort (N = 762, 48% men). Depression-like shifts in cortical gene expression have sex-specific effects on brain morphology and may contribute to broad depression vulnerability in men.

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Cell- and region-specific expression of depression-related protein p11 (S100a10) in the brain.

Publications

Cell- and region-specific expression of depression-related protein p11 (S100a10) in the brain.

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