Podcasts about cdk5

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.09.527850v1?rss=1 Authors: Fadjukov, J., Wienbar, S., Milicevic, N., Hakanen, S., Vihinen-Ranta, M., Ihalainen, T. O., Schwartz, G. W., Nymark, S. Abstract: Retinal pigment epithelium (RPE) at the back of the eye is a monolayer of cells with an extensive network of gap junctions that contributes to retinal health in a multitude of ways. One of those roles is the phagocytosis of photoreceptor outer segments. This renewal is under circadian regulation and peaks after light onset. Connexin 43 (Cx43) is the most predominantly expressed gap junction protein in RPE. In this study, we examine how gap junctions and specifically, Cx43 phosphorylation, contribute to phagocytosis in both human embryonic stem cell derived RPE and mouse RPE monolayers. We show that both Rac1 and CDK5 have differences in protein localization at different points in phagocytosis, and that by using their effectors, the capability of RPE for phagocytosis changes. CDK5 has not yet been reported in RPE tissue, and here we show that it likely regulates Cx43 localization and resulting electrical coupling. We find that gap junctions in RPE are temporally highly dynamic during phagocytosis and that regulation of gap junctions via phosphorylation is likely critical for maintaining eye health. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.31.514565v1?rss=1 Authors: Pinzi, L., Conze, C., Bisi, N., Torre, G. D., Monteiro-Abreu, N., Trushina, N. I., Soliman, A., Krusenbaum, A., Dolouei, M. K., Hellwig, A., Christodoulou, M. S., Passarella, D., Bakota, L., Rastelli, G., Brandt, R. Abstract: Tauopathies such as Alzheimers disease are characterized by the aggregation and increased phosphorylation of the microtubule-associated protein tau. The pathological changes in tau are closely linked to neurodegeneration, making tau a prime candidate for intervention. However, the multiple facets of tau function and the lack of cellular tauopathy models that could support mechanism-based drug development hampers progress. Here we report the development of a live-cell imaging approach to quantitatively monitor pathological changes of human tau as it interacts with axonal microtubules. We show that a full-length aggregation-prone tau construct exhibits reduced interaction with microtubules as it increasingly aggregates. Through chemoinformatic analyses, we identified 2-phenyloxazole (PHOX) derivatives as putative polypharmacological small molecules that inhibit tau aggregation and modulate tau phosphorylation. We found that PHOX15 restores the physiological microtubule interaction of aggregation-prone tau in neurons and inhibits the first phase of tau aggregation in vitro. Furthermore, we report that PHOX15 inhibits the tau kinases GSK3beta and Cdk5, alters the kinome activity of model neurons, and reduces tau phosphorylation at disease-relevant sites. Molecular dynamics simulations highlight cryptic channel-like pockets crossing tau protofilaments and indicate that the binding of PHOX15 in one of the channels reduces the protofilaments ability to adopt a PHF-like conformation. The data show that our imaging approach provides a useful tool for identifying compounds that modulate tau-microtubule interaction in axons. We demonstrate that a polypharmacological approach to simultaneously treat tau aggregation and tau phosphorylation is able to restore physiological microtubule regulation, identifying PHOX15 as a promising drug candidate to counteract tau-induced neurodegeneration. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

An article was just recently published out on social media a couple of weeks ago (June), that talks about a class of drugs called CDK5 Inhibitors. What laypeople may want to know about this study, and this problem in general, is the role of CDK5 (Cyclin-dependent kinase 5) in multiple health problems, and how this latest development might lead to new methods that may bring relief to people. The details are a bit hard-science crunchy, but in summary it is a protein (an enzyme) that affects not only a lot of brain functions, but also some physiological functions as well, including Alzheimer's, MS, and fighting Cancer. Tonight, we will discuss: What is CDK5, and its role in multiple health conditionsPossibilities for CDK5 Inhibitors in Future MedicineCounterpoints and CritiquesConclusions, Closing Remarks, & Final Suggestions We'll start off the evening with some topic-relevant Classic Rock played by Dr. Mathis, followed by Classic Rock trivia in "The Rock & Roll Shrink Recalls," followed by our topic discussion.

Currently, there are about 50 million people with Alzheimer's, 50 million people with Dementia and 10 million people with Parkinson's disease. Unfortunately, these disorders are difficult to treat, and many remain incurable. The existing treatments for Alzheimer's (AD) have limited effectiveness and focus primarily on relieving symptoms rather than slowing the underlying disease. There is a major demand for new treatments, but despite significant efforts, few drug candidates have shown promising results. On this Disruption Everywhere podcast, we will be discussing how a protein called CDK5, has a significant influence on brain function, a key target for treating multiple neurodegenerative diseases with Dr. Kent Werner, Founder and CEO of Cogentis Therapeutics. Listen in on how Cogentis groundbreaking research discovers and develops first-in-class therapeutics that prevent neurodegeneration and restore brain function to benefit the lives of those patients and their families. --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app Support this podcast: https://anchor.fm/disruptioneverywhere/support

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.19.258236v1?rss=1 Authors: Stojakovic, A., Chang, S.-Y., Nesbitt, J., Pichurin, N. P., Ostroot, M., Trushina, E. Abstract: Background: Accumulation of hyperphosphorylated Tau (pTau) protein is associated with synaptic dysfunction in Alzheimers disease (AD). We previously demonstrated that neuroprotection in familial mouse models of AD could be achieved by targeting mitochondria complex I (MCI) and activating the adaptive stress response. Efficacy of this strategy on pTau-related pathology remained unknown. Objective: To investigate the effect of specific MCI inhibitor tricyclic pyrone compound CP2 on pTau levels, memory function, long term potentiation (LTP), and energy homeostasis in 18-month-old 3xTg-AD mice and explore the potential mechanisms. Methods: CP2 was administered to male and female 3xTg-AD mice from 3.5 - 18 months of age. Cognitive function was assessed using the Morris water maze test. Glucose metabolism was measured in periphery using a glucose tolerance test and in the brain using fluorodeoxyglucose F18 positron-emission tomography (FDG-PET). LTP was evaluated using electrophysiology in the hippocampus. The expression of key proteins associated with neuroprotective mechanisms were assessed by western blotting. Results: Chronic CP2 treatment restored synaptic activity and cognitive function, increased levels of synaptic proteins, improved glucose metabolism and energy homeostasis in male and female 3xTg-AD mice. Significant reduction of human pTau in the brain was associated with increased activity of protein phosphatase of type 2A (PP2A), reduced activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3{beta} (GSK3{beta}). Conclusion: CP2 treatment protected against synaptic dysfunction and memory impairment in symptomatic 3xTg-AD mice, and reduced levels of human pTau, indicating that targeting mitochondria with small molecule specific MCI inhibitors represents a promising strategy for AD. Copy rights belong to original authors. Visit the link for more info

Dr. McLinden oversees the non-pharmacological Alzheimer’s Disease and related dementias clinical trials portfolio at the National Institute on Aging. Her portfolio is focused on behavioral, diet, and exercise interventions and devices to prevent, delay, and treat AD. Prior to joining NIA at the end of 2016, she was a program analyst at the National Institute of Mental Health (NIMH) helping to manage the FAST and RAPID clinical trials contracts. As a program officer at NIMH, she oversaw neuroinflammation and training grant portfolios, as well as the NIMH Loan Repayment Program. Dr. McLinden received her PhD in experimental psychology, with a concentration in behavioral neuroscience from Texas Christian University where she conducted research focused on understanding the effects of neuroinflammation on learning and memory in the aging rodent brain. She went on to receive postdoctoral training as a fellow in the NINDS Intramural Research Program where she researched the role of Cdk5 protein in aging and neurodegeneration.

Dr. McLinden oversees the non-pharmacological Alzheimer’s Disease and related dementias clinical trials portfolio at the National Institute on Aging. Her portfolio is focused on behavioral, diet, and exercise interventions and devices to prevent, delay, and treat AD. Prior to joining NIA at the end of 2016, she was a program analyst at the National Institute of Mental Health (NIMH) helping to manage the FAST and RAPID clinical trials contracts. As a program officer at NIMH, she oversaw neuroinflammation and training grant portfolios, as well as the NIMH Loan Repayment Program.Dr. McLinden received her PhD in experimental psychology, with a concentration in behavioral neuroscience from Texas Christian University where she conducted research focused on understanding the effects of neuroinflammation on learning and memory in the aging rodent brain. She went on to receive postdoctoral training as a fellow in the NINDS Intramural Research Program where she researched the role of Cdk5 protein in aging and neurodegeneration.

The Latest Malaria News, in 60 Seconds. CDK5 regulates atypical cell division in gametogony and is essential for DNA replication, and researchers assess whether two experimental vaccines can be combined to create a multistage vaccine against malaria. More: www.fightmalaria.uk/MalariaMinute

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.12.090472v1?rss=1 Authors: Seo, J., Pao, P.-C., Kritskiy, O., Lee, A., Patnaik, D., Watson, L. A., Bula, M., Barker, S. J., Penney, J., Silva, M. C., Haggarty, S. J., Tsai, L.-H. Abstract: Aberrant activity of cyclin-dependent kinase (Cdk5) has been implicated in various neurodegenerative diseases. This effect is mediated by pathological cleavage of the Cdk5 activator p35 to produce the truncated product p25, exhibiting increased stability and altered substrate specificity. The benefit of blocking p25 production has been demonstrated in various rodent and human neurodegenerative models. However, important Cdk5/p35 functions in the developing and adult brain have made it challenging to selectively target the detrimental effects of Cdk5/p25 while sparing the physiological functions of Cdk5/p35. Here, we report a 12-amino acid-long peptide fragment derived from Cdk5 (the Cdk5 inhibitory (Cdk5i) peptide) that shows a high binding affinity toward the Cdk5/p25 complex and can efficiently and selectively inhibit Cdk5/p25 kinase activity. Using cellular assays, mouse neurodegeneration models and human cerebral organoids generated from patient-derived iPSCs, we demonstrate beneficial effects of the Cdk5i peptide on various pathological phenotypes including gliosis, DNA damage, and Tau hyperphosphorylation. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.12.090605v1?rss=1 Authors: Peng, Z., Huang, W.-C., Chen, M., Penney, J., Cam, H., Abdurrob, F., Akay, L., Chen, X., Ralvenius, W., Rubino, L. P., Tsai, L.-H. Abstract: Cyclin dependent kinase 5 (Cdk5) regulates various developmental and physiological processes in the central nervous system. Deregulation of Cdk5 activity in neurons induces severe neurodegeneration and has been implicated in Alzheimers disease (AD) and other neurodegenerative conditions. A large fraction of AD risk genes are highly expressed in microglia, highlighting an important role for these cells in AD pathogenesis. While Cdk5 function in neurons is well characterized, our understanding of its roles in microglial function under physiological and neurodegenerative conditions remain rudimentary. Here, we investigate the roles of Cdk5 in microglia using myeloid-specific Cdk5 conditional knockout mice. Using microglia-specific transcriptome profiling, histological analyses, and behavioral assessments, we found that knockout of Cdk5 in microglia for 1 month induced transcriptional changes characterized by upregulation of cell cycle processes and type I interferon signaling genes in both physiological conditions and AD-related amyloidogenesis. In contrast to the robust transcriptional changes, conditional loss of microglial Cdk5 produced minimal effects on the density and morphology of microglia and their phagocytic activity toward myelin debris. Moreover, Cdk5cKO mice exhibited little change in synaptic density and tasks associated with locomotor, anxiety-like, and memory-related behaviors. Our findings indicate that the conditional loss of Cdk5 in microglia induces rapid alterations of microglial transcriptome with minimal or delayed effects on histological and behavioral responses. Copy rights belong to original authors. Visit the link for more info

Theo Rein explains how the antidepressant paroxetine affects epigenetic regulation of Bdnf.

For a long time cyclin dependent kinase 5 (Cdk5) was thought to be of exclusive importance in neuronal cells. However, recently increasing evidence suggests a function of Cdk5 in cancer progression. In the present study, we examined the role of Cdk5 in hepatocellular carcinoma (HCC), a highly chemoresistant cancer with poor prognosis. Consequently, development of novel targeted therapies for HCC is of paramount clinical importance. Analysis of human HCC patient samples showed an increased expression of Cdk5 as compared to normal liver tissues. Functional ablation of Cdk5 significantly decreases HCC cell proliferation and clonogenic survival, and reduces cell motility and invasion. Of note, genetic as well as pharmacologic inhibition of Cdk5 also shows in vivo efficacy in a HCC xenograft mouse model. Investigating the mechanism behind these functional effects revealed that Cdk5 is most active in the nucleus of cells in G2/M phase. In this cell cycle phase DNA damage response takes place, which is affected by Cdk5 inhibition. Furthermore, Cdk5 leads to phosphorylation of Ataxia Telangiectasia Mutated (ATM) and thereby influence its downstream signaling. Importantly, combination of Cdk5 inhibition with different DNA damage inducing chemotherapeutics or the first-line systemic drug sorafenib inhibits synergistically HCC tumor progression. In conclusion, we introduce: 1. Cdk5 as a novel drugable target for treatment of HCC 2. The combination of Cdk5 inhibition and DNA damage agents as a novel therapeutic approach 3. An increased efficacy of sorafenib treatment by combing with Cdk5 inhibition

Tue, 25 Oct 2011 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/13648/ https://edoc.ub.uni-muenchen.de/13648/1/Weitensteiner_Sabine.pdf Weitensteiner, Sabine

A cell-based, high-throughput screen identifies activators and inhibitors of invadopodia formation.