Biology subjects

Brenna, A.

Publications and source records attributed to Brenna, A..

5 recordsLinked to original sources

bioRxiv2024

Cyclin-dependent kinase 5 (Cdk5) activity is modulated by light and gates rapid phase shifts of the circadian clock

The circadian clock enables organisms to synchronize biochemical and physiological processes over a 24-hour period. Natural changes in lighting conditions, as well as artificial disruptions like jet lag or shift work, can advance or delay the clock phase to align physiology with the environment. Within the suprachiasmatic nucleus (SCN) of the hypothalamus, circadian timekeeping and resetting rely on both membrane depolarization and intracellular second-messenger signaling. Voltage-gated calcium channels (VGCCs) facilitate calcium influx in both processes, activating intracellular signaling pathways that trigger Period (Per) gene expression. However, the precise mechanism by which these processes are concertedly gated remains unknown. Our study demonstrates that cyclin-dependent kinase 5 (Cdk5) activity is modulated by light and regulates phase shifts of the circadian clock. We observed that knocking down Cdk5 in the SCN of mice affects phase delays but not phase advances. This is linked to uncontrolled calcium influx into SCN neurons and an unregulated protein kinase A (PKA) - calcium/calmodulin-dependent kinase (CaMK) - cAMP response element-binding protein (CREB) signaling pathway. Consequently, genes such as Per1 are not induced by light in the SCN of Cdk5 knock-down mice. Our experiments identified Cdk5 as a crucial light-modulated kinase that influences rapid clock phase adaptation. This finding elucidates how light responsiveness and clock phase coordination adapt activity onset to seasonal changes, jet lag, and shift work.

neuroscience↗

bioRxiv2024

Cell-autonomous and non-cell-autonomous effects of arginase-II on cardiac aging

Aging is a predominant risk factor for heart disease. Aging heart reveals low-grade chronic inflammation, cell apoptosis, cardiac fibrosis, and increased vulnerability to ischemic injury. The underlying molecular mechanisms responsible for the cardiac aging phenotype and its susceptibility to injury are far from being fully understood. Although previous literature reports a role of the mitochondrial enzyme arginase-II (Arg-II) in development of heart failure, contradictory results are reported and no systematic analysis of cellular expression and localization of Arg-II in the heart has been performed. Whether and how Arg-II participates in cardiac aging are still unknown. In this study, we demonstrate, to our surprise, that Arg-II is not expressed in cardiomyocytes from aged mice and human patients, but upregulated in non-myocytes of the aging heart, including macrophages, fibroblasts, endothelial cells. Mice with genetic deficiency of arg-ii (arg-ii-/-) are protected from age-associated cardiac inflammation, myocyte apoptosis, interstitial and perivascular fibrosis, endothelial-mesenchymal transition (EndMT), and susceptibility to ischemic injury. Further experiments show that Arg-II mediates IL-1{beta} release from macrophages of old mice, contributing to the above-described cardiac aging phenotype. In addition, Arg-II enhances mitochondrial reactive oxygen species (mtROS) and activates cardiac fibroblasts that is inhibited by inhibition of mtROS. Thus, our study demonstrates a non-cell-autonomous effect of Arg-II on cardiomyocytes, fibroblasts, and endothelial cells mediated by IL-1{beta} from aging macrophages as well as a cell-autonomous effect of Arg-II through mtROS in fibroblasts contributing to cardiac aging phenotype.

physiology↗

bioRxiv2021

CDK5 influences the organization of the Circadian Machinery in peripheral clocks.

Circadian rhythms are self-sustained physiological changes that drive rhythmicity within the 24-hours cycles. Posttranslational modifications (PMTs), such as protein phosphorylation, acetylation, sumoylation, and ubiquitination, are biochemical processes that modify protein structure and functions, ensuring circadian rhythm precision. For example, phosphorylation is considered the most important hallmark of rhythmicity from cyanobacteria to mammals. Cyclin-dependent kinase 5 (CDK5) has been shown to regulate the mammalian SCNs circadian clock via phosphorylation of PER2. Here, we show that CDK5 influences the clock machinery assembling, using immortalized mouse embryonic fibroblast as an in vitro model for studying the peripheral clock. In fact, the circadian period at the cellular level is lengthened. Furthermore, the clock-controlled genes expression amplitude is dampened in Cdk5 ko cell lines, while the phase is delayed about 4 hours. Taken together, we show in vitro that CDK5 is critically involved in regulating the peripheral clocks, influencing their temporal and spatial dynamics.

molecular biology↗

bioRxiv2020

Light affects behavioral despair involving the clock gene Period 1

Light at night has strong effects on physiology and behavior of mammals. It affects mood in humans, which is exploited as light therapy, and has been shown to reset the circadian clock in the suprachiasmatic nuclei (SCN). This resetting is paramount to align physiological and biochemical timing to the environmental light-dark cycle. Here we provide evidence that light affects mood-related behaviors also in mice by activating the clock gene Period1 (Per1) in the lateral habenula (LHb), a brain region known to modulate mood-related behaviors. A light pulse given at ZT22 to wild type mice caused profound changes of gene expression in the mesolimbic dopaminergic system including the nucleus accumbens (NAc). Sensory perception of smell and G-protein coupled receptor signaling was affected the most in this brain region. Interestingly, most of these genes were not affected in Per1 knock-out animals, indicating that induction of Per1 by light serves as a filter for light-mediated gene induction in the brain. Taken together we show that light affects mood-related behavior in mice at least in part via induction of Per1 in the LHb with consequences on signaling mechanisms in the mesolimbic dopaminergic system.

genetics↗

bioRxiv2019

Cyclin Dependent Kinase 5 (CDK5) Regulates the Circadian Clock

Circadian oscillations emerge from transcriptional and post-translational feedback loops. An important step in generating rhythmicity is the translocation of clock components into the nucleus, which is regulated in many cases by kinases. In mammals, the kinase promoting the nuclear import of the key clock component Period 2 (PER2) is unknown. Here we show that the cyclin-dependent kinase 5 (CDK5) regulates the mammalian circadian clock involving phosphorylation of PER2. Knock-down of Cdk5 in the suprachiasmatic nuclei (SCN), the main coordinator site of the mammalian circadian system, shortened the free-running period in mice. CDK5 phosphorylated PER2 at serine residue 394 (S394) in a diurnal fashion. This phosphorylation facilitated interaction with Cryptochrome 1 (CRY1) and nuclear entry of the PER2-CRY1 complex. Taken together, we found that CDK5 drives nuclear entry of PER2, which is critical for establishing an adequate circadian period of the molecular circadian cycle. Therefore, CDK5 is critically involved in the regulation of the circadian clock and may represent a link to various diseases affected by the circadian clock.

neuroscience↗