Functional Genomic and Proteomic Analysis Reveals Disruption of Myelin-Related Genes and Translation in a Mouse Model of Early Life Neglect

Bordner, Kelly A.; George, Elizabeth D.; Carlyle, Becky C.; Duque, Alvaro; Kitchen, Robert; Lam, TuKiet T.; Colangelo, Christopher M.; Stone, Kathryn L.; Abbott, Thomas; Mane, Shrikant; Nairn, Angus C.; Simen, Arthur A.

doi:10.3389/fpsyt.2011.00018

Cited by 58 publications

(67 citation statements)

References 103 publications

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“…To identify all the major protein changes in ANCL brains, we performed high resolution LC-MS/MS based label-free quantification (LFQ) [6] on human control and CLN4 patient cortical brain samples. One L115R and one L116 patient sample each with age matched controls were used to examine the protein changes in CLN4 brains.…”

Section: Resultsmentioning

confidence: 99%

Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation

et al. 2015

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Neuronal Ceroid Lipofuscinoses (NCL) are a group of inherited neurodegenerative disorders with lysosomal pathology (CLN1-14). Recently, mutations in the DNAJC5/CLN4 gene, which encodes the presynaptic co-chaperone CSP were shown to cause autosomal-dominant NCL. Although 14 NCL genes have been identified, it is unknown if they act in common disease pathways. Here we show that two disease-associated proteins, CSPα and the depalmitoylating enzyme palmitoyl-protein thioesterase 1 (PPT1/CLN1) are biochemically linked. We find that in DNAJC5/CLN4 patient brains, PPT1 is massively increased and mis-localized. Surprisingly, the specific enzymatic activity of PPT1 is dramatically reduced. Notably, we demonstrate that CSP is depalmitoylated by PPT1 and hence its substrate. To determine the consequences of PPT1 accumulation, we compared the palmitomes from control and DNAJC5/CLN4 patient brains by quantitative proteomics. We discovered global changes in protein palmitoylation, mainly involving lysosomal and synaptic proteins. Our findings establish a functional link between two forms of NCL and serve as a springboard for investigations of NCL disease pathways.

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Section: Resultsmentioning

confidence: 99%

Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation

et al. 2015

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“…changes in gene expression, and led to an intensive search for additional genes whose expression in adulthood is modified by early life stress (Benekareddy et al, 2010;Bordner et al, 2011;Erabi et al, 2007;Kohda et al, 2006;van Heerden et al, 2009;Weaver et al, 2006). Here, we hypothesize that in addition to this well-described longterm alteration in gene expression, some long-term consequences of early life stress are due to transient changes in gene expression that disrupt key neurodevelopmental processes that are in turn necessary to support normal brain function and behavior in adulthood.…”

Section: Early Life Stress Inhibits Lbp Expression L Wei Et Almentioning

confidence: 88%

Early Life Stress Inhibits Expression of a Novel Innate Immune Pathway in the Developing Hippocampus

Lan

Simen

Mane

et al. 2011

Neuropsychopharmacol

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Childhood maltreatment represents a major risk factor for the development of numerous childhood psychopathologies that in many cases linger as chronic mental illnesses in adulthood. Exposing rodents or non-human primates to early life stress increases anxiety-like behaviors and impairs cognitive function in adulthood, suggesting that animal models may provide important insights into parallel developmental processes in humans. Using an unbiased genomic screen, we found that expression of lipopolysaccharide binding protein (LBP), a member of the innate immune system, is dramatically decreased in the hippocampus of pups exposed to early life stress. LBP levels peak in the normally developing hippocampus at a period of intense synaptic pruning, during which LBP is colocalized with the synaptic marker PSD95 and is found in close proximity to processes of microglia cells. Expression of LBP declines to low levels seen in adulthood at around postnatal day 30. Importantly, 30-day-old LBP knockout (k.o.) mice show increased spine density and abnormal spine morphology, suggesting that peak levels of LBP during the second and third weeks of life are necessary for normal synaptic pruning in the hippocampus. Finally, LBP k.o. mice show impaired hippocampal-dependent memory and increased anxiety-like behaviors in a manner that resembles that seen in animals exposed to early life stress. These findings describe a novel role for LBP in normal hippocampal development and raise the possibility that at least some of the behavioral sequelae of early life stress are mediated by reduced expression of LBP during a critical period of neurodevelopment.

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“…As detailed elsewhere [15,16] experimentally naive C57 and DBA mice were obtained from Jackson Laboratories (Bar Harbor, ME), and subsequently bred in-house. Entire litters were randomized at birth to control or Maternal Separation with Early Weaning (MSEW) conditions, but only male mice were included in the research.…”

Section: Methodsmentioning

confidence: 99%

“…As described previously [20], mice were anesthetized with chloral hydrate (1500mg/kg in sterile saline, IP) and rapidly decapitated. Whole brain was collected and placed in RNAlater (Qiagen) for 24 h, and then stored at −20 °C.…”

Section: Methodsmentioning

confidence: 99%

The role of genes involved in stress, neural plasticity, and brain circuitry in depressive phenotypes: Convergent findings in a mouse model of neglect

Montalvo-Ortiz

Bordner

Carlyle

et al. 2016

Behavioural Brain Research

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Early life neglect increases risk for the development of psychopathologies during childhood and adulthood, including depression and anxiety disorders. We recently reported epigenetic changes in DNA derived from saliva in three genes predicted depression in a cohort of maltreated children: DNA-binding protein inhibitor ID-3 (ID3), Glutamate NMDA Receptor (GRIN1), and Tubulin Polymerization Promoting Protein (TPPP). To validate the role of these genes in depression risk, secondary analyses were conducted of gene expression data obtained from medial prefrontal cortex (mPFC) tissue of mice subjected to a model of maternal neglect which included maternal separation and early weaning (MSEW). Anxiety and depression-like phenotype data derived using the elevated plus maze (EPM) and forced swimming test (FST), respectively, were also available for secondary analyses. Behavioral tests were conducted in MSEW and control adult male mice when they were between 65 and 80 days old. ID3, GRIN1 and TPPP gene expression in the mPFC were found to significantly predict behavioral differences in the EPM and FST. These results further support the role of these genes in the etiology of depressive and anxiety phenotypes following early life stress.

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Functional Genomic and Proteomic Analysis Reveals Disruption of Myelin-Related Genes and Translation in a Mouse Model of Early Life Neglect

Cited by 58 publications

References 103 publications

Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation

Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation

Early Life Stress Inhibits Expression of a Novel Innate Immune Pathway in the Developing Hippocampus

The role of genes involved in stress, neural plasticity, and brain circuitry in depressive phenotypes: Convergent findings in a mouse model of neglect

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