Altered Patterns of Sleep and Behavioral Adaptability in NPAS2-Deficient Mice

Dudley, Carol A.; Erbel-Sieler, Claudia; Estill, Sandi Jo; Reick, Martin; Franken, Paul; Pitts, SiNae; McKnight, Steven L.

doi:10.1126/science.1082795

Cited by 370 publications

(298 citation statements)

References 49 publications

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“…Mutations in either the FBXL21 or FBXL3 genes can lead to a dysfunction of circadian rhythm oscillations and lead to significant behavioral disturbances in individuals and alterations in their sleeping patterns; moreover the absence of FBXL21 causes a short-period phenotype in both mice and cells (Hirano et al, 2013;Yoo et al, 2013 (Bromundt et al, 2011); which is further supported by a microarray study which found a significant downregulation of the circadian pacemaker gene PER1 in the postmortem temporal cortex of schizophrenia patients compared to healthy controls (Aston et al, 2004). Furthermore, an animal model study has shown dysfunction in the synchronization of circadian rhythms between brain cell networks involved in sleep-wake regulation and cognition (Dudley et al, 2003). Overall this suggests that alterations in circadian rhythms are present in schizophrenia, and that polymorphisms in the FBXL21 gene in addition to the FBX3 gene, could be involved in the circadian cycle disturbances that have been observed in schizophrenia (Mansour et al, 2009).…”

Section: Discussionmentioning

confidence: 71%

Investigation of genetic variants in ubiquitin enzyme genes involved in the modulation of neurodevelopmental processes: a role in schizophrenia susceptibility?

Andrews

Fernandez

2014

Genet. Res.

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Despite extensive research during the last few decades, the etiology of schizophrenia remains unclear. Evidence of both genetic and environmental influences in the developmental profile of schizophrenia has grown, and due to the complexity of this disorder, a polygenic aspect has been associated with this neuropsychiatric pathology. Unfortunately, no diagnostic strategies based on biological measurement or genetic testing is currently available for schizophrenia. Gene-expression profiling and recent protein studies have shown a decrease in the expression of ubiquitin pathway proteins in the prefrontal cortex of schizophrenia patients. We have examined single nucleotide polymorphisms (or SNPs) within three genes from the ubiquitin protein system: the ubiquitin conjugating enzyme E2D1 (UBE2D1) gene, the E3 SUMOprotein ligase protein inhibitor of activated STAT 2 (PIAS2) gene, and the E3 ubiquitin ligase F-box and leucine-rich repeat protein 21 (FBXL21) gene, in a Caucasian case-control population for schizophrenia. After Bonferroni correction for multiple testing was applied, no significant associations were reported for any of the tested SNPs. Additional genetic analyses will be necessary to fully explore the role of these three genes in schizophrenia. Regarding the rising interest in ubiquitin-related proteins as a therapeutic target in other pathologies such as cancer, further research into the role of ubiquitin pathways in schizophrenia seems topical and timely. SummaryDespite extensive research during the last decades, the etiology of schizophrenia remains unclear. Evidence of both genetic and environmental influences in the developmental profile of schizophrenia has grown, and due to the complexity of this disorder, a polygenic aspect has been associated with this neuropsychiatric pathology. Unfortunately, no diagnostic strategies based on biological measurement or genetic testing is currently available for schizophrenia. Gene expression profiling and recent protein studies have shown a decrease in the expression of ubiquitin pathway proteins in the prefrontal cortex of schizophrenia patients. We have examined Single Nucleotide Polymorphisms (or SNPs) within three genes from the ubiquitin protein system: the ubiquitin conjugating enzyme E2D1 (UBE2D1) gene, the E3 SUMO-protein ligase protein inhibitor of activated STAT 2 (PIAS2) gene, and the E3 ubiquitin ligase F-box and leucine-rich repeat protein 21 (FBXL21) gene, in a Caucasian case-control population for schizophrenia. After Bonferroni correction for multiple testing was applied, no significant associations were reported for any of the tested SNPs. Additional genetic analyses will be necessary to fully explore the role of these three genes in schizophrenia. Regarding the rising interest of ubiquitin related proteins as a therapeutic target in other pathologies such as cancer, further research into the role of ubiquitin pathways in schizophrenia seem topical and timely.

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Section: Discussionmentioning

confidence: 71%

Investigation of genetic variants in ubiquitin enzyme genes involved in the modulation of neurodevelopmental processes: a role in schizophrenia susceptibility?

Andrews

Fernandez

2014

Genet. Res.

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“…NPAS2 forms heterodimers with BMAL1 and then transcriptionally activates expression of the circadian genes per and cry, which are required for maintaining biological rhythms in many organisms [6,7]. In animal studies, altered circadian patterns of sleep and behavioral adaptability have been observed in NPAS2-deficient mice [8].…”

Section: Introductionmentioning

confidence: 99%

Non-synonymous polymorphisms in the circadian gene NPAS2 and breast cancer risk

Zhu

Stevens

Leaderer

et al. 2007

Breast Cancer Res Treat

102

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Three known non-synonymous polymorphisms (Ala394Thr, Ser471Leu and Pro690Ala) in the largest circadian gene, Neuronal PAS domain protein 2 (NPAS2), were genotyped in a breast cancer case-control study conducted in Connecticut, USA (431 cases and 476 controls). We found that women with the heterozygous Ala394Thr genotype were significantly associated with breast cancer risk compared to those with the common homozygous Ala394Ala (OR = 0.61, 0.46-0.81, P = 0.001). This is the first evidence demonstrating a role of the circadian gene NPAS2 in human breast cancer, suggesting that genetic variations in circadian genes might be a novel panel of biomarkers for breast cancer risk.

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“…Several studies show that the molecular regulators of the circadian clock have different influences on sleep patterns. For example, in NPAS2-deficient mice, non-REM sleep is reduced and more sleep time is required following sleep deprivation [98]. But the absence of Cry1, 2 is characterized by hypersomnolence [99].…”

Section: Clock Gene Differencementioning

confidence: 99%

A New Perspective for Parkinson’s Disease: Circadian Rhythm

Wang

et al. 2016

Neurosci. Bull.

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Circadian rhythm is manifested by the behavioral and physiological changes from day to night, which is controlled by the pacemaker and its regulator. The former is located at the suprachiasmatic nuclei (SCN) in the anterior hypothalamus, while the latter is composed of clock genes present in all tissues. Circadian desynchronization influences normal patterns of day-night rhythms such as sleep and alertness cycles, rest and activity cycles. Parkinson's disease (PD) exhibits diurnal fluctuations. Circadian dysfunction has been observed in PD patients and animal models, which may result in negative consequences to the homeostasis and even exacerbate the disease progression. Therefore, circadian therapies, including light stimulation, physical activity, dietary and social schedules, may be helpful for PD patients. However, the cellular and molecular mechanisms that underlie the circadian dysfunction in PD remain elusive. Further research on circadian patterns is needed. This article summarizes the existing research on the circadian rhythms in PD, focusing on the clinical symptom variations, molecular changes, as well as the available treatment options.

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Altered Patterns of Sleep and Behavioral Adaptability in NPAS2-Deficient Mice

Cited by 370 publications

References 49 publications

Investigation of genetic variants in ubiquitin enzyme genes involved in the modulation of neurodevelopmental processes: a role in schizophrenia susceptibility?

Investigation of genetic variants in ubiquitin enzyme genes involved in the modulation of neurodevelopmental processes: a role in schizophrenia susceptibility?

Non-synonymous polymorphisms in the circadian gene NPAS2 and breast cancer risk

A New Perspective for Parkinson’s Disease: Circadian Rhythm

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