CRY1 and CRY2 genetic variants in seasonality: A longitudinal and cross-sectional study

Kovanen, Leena; Donner, Kati; Kaunisto, Mari A.; Partonen, Timo

doi:10.1016/j.psychres.2016.05.044

Cited by 11 publications

(9 citation statements)

References 55 publications

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“…3) between medaka kept under winter-and summer-like conditions. Candidate gene studies for SAD also reported SNPs in circadian clock genes, including PER2, PER3, BMAL1, CLOCK, NPAS2, and CRY2 (30)(31)(32)(33)(34). We demonstrated a significant decrease in the amplitude of circadian clock gene rhythms in medaka kept under winter-like conditions compared to those in summer-like conditions (Figs.…”

Section: Discussionsupporting

confidence: 56%

Seasonal changes in NRF2 antioxidant pathway regulates winter depression-like behavior

Nakayama

Okimura

Shen

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Seasonal changes in the environment lead to depression-like behaviors in humans and animals. The underlying mechanisms, however, are unknown. We observed decreased sociability and increased anxiety-like behavior in medaka fish exposed to winter-like conditions. Whole brain metabolomic analysis revealed seasonal changes in 68 metabolites, including neurotransmitters and antioxidants associated with depression. Transcriptome analysis identified 3,306 differentially expressed transcripts, including inflammatory markers, melanopsins, and circadian clock genes. Further analyses revealed seasonal changes in multiple signaling pathways implicated in depression, including the nuclear factor erythroid-derived 2-like 2 (NRF2) antioxidant pathway. A broad-spectrum chemical screen revealed that celastrol (a traditional Chinese medicine) uniquely reversed winter behavior. NRF2 is a celastrol target expressed in the habenula (HB), known to play a critical role in the pathophysiology of depression. Another NRF2 chemical activator phenocopied these effects, and an NRF2 mutant showed decreased sociability. Our study provides important insights into winter depression and offers potential therapeutic targets involving NRF2.

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Section: Discussionsupporting

confidence: 56%

Seasonal changes in NRF2 antioxidant pathway regulates winter depression-like behavior

Nakayama

Okimura

Shen

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Several genetic studies have highlighted the relationship between CRY variants and different types of diseases. For example, CRY1 variants have been associated with depression and mood disorders (48)(49)(50), elevated blood pressure and hypertension (49), and insulin resistance (51,52). This clinical heterogeneity implies a variety of different functions for CRY1, potentially caused by different functional domains of the protein.…”

Section: Discussionmentioning

confidence: 99%

The Arg-293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm

Gül

Aydın

Ozcan

et al. 2020

Journal of Biological Chemistry

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Mammalian circadian clocks are driven by transcription/translation feedback loops composed of positive transcriptional activators (BMAL1 and CLOCK) and negative repressors (CRYPTOCHROMEs (CRYs) and PERIODs (PERs)). CRYs, in complex with PERs, bind to the BMAL1/CLOCK complex and repress E-box driven transcription of clock associated genes. There are two individual CRYs, with CRY1 exhibiting higher affinity to the BMAL1/CLOCK complex than CRY2. It is known that this differential binding is regulated by a dynamic serine-rich loop adjacent to the secondary pocket of both CRYs, but the underlying features controlling loop dynamics are not known. Here we report that allosteric regulation of the serine-rich loop is mediated by Arg293 of CRY1, identified as a rare CRY1 SNPs in the Ensembl and 1000 Genomes databases. The p.Arg293His CRY1 variant caused a shortened circadian period in a Cry1-/-Cry2-/-double knockout mouse embryonic fibroblast cell line. Moreover, the variant displayed reduced repressor activity on BMAL1/CLOCK driven transcription, which is explained by reduced affinity to BMAL1/CLOCK in the absence of PER2 compared to wild type CRY1. Molecular dynamics simulations revealed that the p.Arg293His CRY1 variant altered a communication pathway between Arg293 and the serine loop, by reducing its dynamicity. Collectively, this study provides direct evidence that allosterism in CRY1 is critical for the regulation of circadian rhythm.

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“…Kraus et al ( 27 ) determined that although the age at which mortality started increasing did not differ across small and large breeds, once senescence begins, big dog breeds do age more rapidly than small ones. However, Salvin et al ( 17 ) found little evidence for an increased rate of behavioral aging in large, short-lived dogs utilizing a cross-sectional survey, perhaps due to the shorter window of senescence onset and mortality in large breed dogs.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, mixed breed dogs are often assumed to have a phenotypic advantage over pure breeds, resulting in greater longevity, improved health and lower susceptibility to diseases due to higher genetic variation ( 26 , 29 , 35 – 37 ). However, Salvin et al ( 17 ) found no evidence for differences between pure breed and cross breed dogs in behavioral aging, and health status is dependent almost exclusively on age with no detectable effect of breed ( 34 ). But specific types of morbidities have been found to be breed specific, such as mast cell tumor, lymphoma, granulomatous colitis, and idiopathic epilepsy ( 33 , 38 ).…”

Section: Introductionmentioning

confidence: 99%

Demographic Change Across the Lifespan of Pet Dogs and Their Impact on Health Status

et al. 2018

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Although dogs' life expectancies are six to twelve times shorter than that of humans, the demographics (e. g., living conditions) of dogs can still change considerably with aging, similarly to humans. Despite the fact that the dog is a particularly good model for human healthspan, and the number of aged dogs in the population is growing in parallel with aged humans, there has been few previous attempts to describe demographic changes statistically. We utilized an on-line questionnaire to examine the link between the age and health of the dog, and owner and dog demographics in a cross-sectional Hungarian sample. Results from univariate analyses revealed that 20 of the 27 demographic variables measured differed significantly between six dog age groups. Our results revealed that pure breed dogs suffered from health problems at a younger age, and may die at an earlier age than mixed breeds. The oldest dog group (>12 years) consisted of fewer pure breeds than mixed breeds and the mixed breeds sample was on average older than the pure breed sample. Old dogs were classified more frequently as unhealthy, less often had a “normal” body condition score, and more often received medication and supplements. They were also more often male, neutered, suffered health problems (such as sensory, joint, and/or tooth problems), received less activity/interaction/training with the owner, and were more likely to have experienced one or more traumatic events. Surprisingly, the youngest age group contained more pure breeds, were more often fed raw meat, and had owners aged under 29 years, reflecting new trends among younger owners. The high prevalence of dogs that had experienced one or more traumatic events in their lifetime (over 40% of the sample), indicates that welfare and health could be improved by informing owners of the greatest risk factors of trauma, and providing interventions to reduce their impact. Experiencing multiple life events such as spending time in a shelter, changing owners, traumatic injury/prolonged disease/surgery, getting lost, and changes in family structure increased the likelihood that owners reported that their dogs currently show behavioral signs that they attribute to the previous trauma.

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CRY1 and CRY2 genetic variants in seasonality: A longitudinal and cross-sectional study

Cited by 11 publications

References 55 publications

Seasonal changes in NRF2 antioxidant pathway regulates winter depression-like behavior

Seasonal changes in NRF2 antioxidant pathway regulates winter depression-like behavior

The Arg-293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm

Demographic Change Across the Lifespan of Pet Dogs and Their Impact on Health Status

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