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4. Aging and drug discovery

Author

Bakula, Daniela, Aliper, Alexander M, Mamoshina, Polina, Petr, Michael A, Teklu, Amanuel, Baur, Joseph A, Campisi, Judith, Ewald, Collin Y, Georgievskaya, Anastasia, Gladyshev, Vadim N, Kovalchuk, Olga, Lamming, Dudley W, Luijsterburg, Martijn S, Martín-Montalvo, Alejandro, Maudsley, Stuart, Mkrtchyan, Garik V, Moskalev, Alexey, Olshansky, S Jay, Ozerov, Ivan V, Pickett, Alexander, Ristow, Michael, Zhavoronkov, Alex, and Scheibye-Knudsen, Morten

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Clinical Sciences, Biological Sciences, Aging, 5.1 Pharmaceuticals, 5.9 Resources and infrastructure (treatment development), Generic health relevance, Good Health and Well Being, aging, drug discovery, Biochemistry and cell biology, Clinical sciences
Abstract

Multiple interventions in the aging process have been discovered to extend the healthspan of model organisms. Both industry and academia are therefore exploring possible transformative molecules that target aging and age-associated diseases. In this overview, we summarize the presented talks and discussion points of the 5th Annual Aging and Drug Discovery Forum 2018 in Basel, Switzerland. Here academia and industry came together, to discuss the latest progress and issues in aging research. The meeting covered talks about the mechanistic cause of aging, how longevity signatures may be highly conserved, emerging biomarkers of aging, possible interventions in the aging process and the use of artificial intelligence for aging research and drug discovery. Importantly, a consensus is emerging both in industry and academia, that molecules able to intervene in the aging process may contain the potential to transform both societies and healthcare.

Published
2018

6. USP20 deletion promotes eccentric cardiac remodeling in response to pressure overload and increases mortality.

Author

Jean-Charles, Pierre-Yves, Roy, Bipradas, Yu, Samuel Mon-Wei, Pironti, Gianluigi, Nagi, Karim, Mao, Lan, Kaur, Suneet, Abraham, Dennis M., Maudsley, Stuart, Rockman, Howard A., and Shenoy, Sudha K.

Subjects
MOLECULAR motor proteins, LEFT ventricular hypertrophy, CARDIAC hypertrophy, DEUBIQUITINATING enzymes, HEART failure, CARDIOVASCULAR diseases risk factors
Abstract

Left ventricular hypertrophy (LVH) caused by chronic pressure overload with subsequent pathological remodeling is a major cardiovascular risk factor for heart failure and mortality. The role of deubiquitinases in LVH has not been well characterized. To define whether the deubiquitinase ubiquitin-specific peptidase 20 (USP20) regulates LVH, we subjected USP20 knockout (KO) and cognate wild-type (WT) mice to chronic pressure overload by transverse aortic constriction (TAC) and measured changes in cardiac function by serial echocardiography followed by histological and biochemical evaluations. USP20-KO mice showed severe deterioration of systolic function within 4 wk of TAC compared with WT cohorts. Both USP20-KO TAC and WT-TAC cohorts presented cardiac hypertrophy following pressure overload. However, USP20-KO-TAC mice showed an increase in cardiomyocyte length and developed maladaptive eccentric hypertrophy, a phenotype generally observed with volume overload states and decompensated heart failure. In contrast, WT-TAC mice displayed an increase in cardiomyocyte width, producing concentric remodeling that is characteristic of pressure overload. In addition, cardiomyocyte apoptosis, interstitial fibrosis, and mouse mortality were augmented in USP20-KO-TAC compared with WT-TAC mice. Quantitative mass spectrometry of LV tissue revealed that the expression of sarcomeric myosin heavy chain 7 (MYH7), a fetal gene normally upregulated during cardiac remodeling, was significantly reduced in USP20-KO after TAC. Mechanistically, we identified increased degradative lysine-48 polyubiquitination of MYH7 in USP20-KO hearts, indicating that USP20-mediated deubiquitination likely prevents protein degradation of MYH7 during pressure overload. Our findings suggest that USP20-dependent signaling pathways regulate the layering pattern of sarcomeres to suppress maladaptive remodeling during chronic pressure overload and prevent cardiac failure. NEW & NOTEWORTHY: We identify ubiquitin-specific peptidase 20 (USP20) as an important enzyme that is required for cardiac homeostasis and function, particularly during myocardial pressure overload. USP20 regulates protein stability of cardiac MYH7, an essential molecular motor protein expressed in sarcomeres; loss-of-function mutations of MYH7 are associated with human hypertrophic cardiomyopathy, cardiac failure, and sudden death. Enhancing USP20 activity could be a potential therapeutic approach to prevent the development of maladaptive state of eccentric hypertrophy and heart failure. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Hippocampal Transcriptomic and Proteomic Alterations in the BTBR Mouse Model of Autism Spectrum Disorder.

Author

Daimon, Caitlin M, Jasien, Joan M, Wood, William H, Zhang, Yongqing, Becker, Kevin G, Silverman, Jill L, Crawley, Jacqueline N, Martin, Bronwen, and Maudsley, Stuart

Subjects
BTBR mouse model, autism spectrum disorder phenotype, behavior, bioinformatics, etiology, Physiology, Medical Physiology, Psychology
Abstract

Autism spectrum disorders (ASD) are complex heterogeneous neurodevelopmental disorders of an unclear etiology, and no cure currently exists. Prior studies have demonstrated that the black and tan, brachyury (BTBR) T+ Itpr3tf/J mouse strain displays a behavioral phenotype with ASD-like features. BTBR T+ Itpr3tf/J mice (referred to simply as BTBR) display deficits in social functioning, lack of communication ability, and engagement in stereotyped behavior. Despite extensive behavioral phenotypic characterization, little is known about the genes and proteins responsible for the presentation of the ASD-like phenotype in the BTBR mouse model. In this study, we employed bioinformatics techniques to gain a wide-scale understanding of the transcriptomic and proteomic changes associated with the ASD-like phenotype in BTBR mice. We found a number of genes and proteins to be significantly altered in BTBR mice compared to C57BL/6J (B6) control mice controls such as BDNF, Shank3, and ERK1, which are highly relevant to prior investigations of ASD. Furthermore, we identified distinct functional pathways altered in BTBR mice compared to B6 controls that have been previously shown to be altered in both mouse models of ASD, some human clinical populations, and have been suggested as a possible etiological mechanism of ASD, including "axon guidance" and "regulation of actin cytoskeleton." In addition, our wide-scale bioinformatics approach also discovered several previously unidentified genes and proteins associated with the ASD phenotype in BTBR mice, such as Caskin1, suggesting that bioinformatics could be an avenue by which novel therapeutic targets for ASD are uncovered. As a result, we believe that informed use of synergistic bioinformatics applications represents an invaluable tool for elucidating the etiology of complex disorders like ASD.

Published
2015

12. Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice.

Author

Mirsoian, Annie, Bouchlaka, Myriam, Sckisel, Gail, Chen, Mingyi, Pai, Chien-Chun, Maverakis, Emanuel, Spencer, Richard, Fishbein, Kenneth, Siddiqui, Sana, Monjazeb, Arta, Martin, Bronwen, Maudsley, Stuart, Hesdorffer, Charles, Ferrucci, Luigi, Longo, Dan, Blazar, Bruce, Wiltrout, Robert, Taub, Dennis, and Murphy, William

Subjects
Adiposity, Aging, Animals, Caloric Restriction, Cytokines, Female, Flow Cytometry, Humans, Immunotherapy, Inflammation Mediators, Intra-Abdominal Fat, Macrophages, Mice, Inbred C57BL, Mice, Obese, Neoplasms, Obesity, Tumor Necrosis Factor-alpha
Abstract

Aging is a contributing factor in cancer occurrence. We recently demonstrated that systemic immunotherapy (IT) administration in aged, but not young, mice resulted in induction of rapid and lethal cytokine storm. We found that aging was accompanied by increases in visceral fat similar to that seen in young obese (ob/ob or diet-induced obese [DIO]) mice. Yet, the effects of aging and obesity on inflammatory responses to immunotherapeutics are not well defined. We determine the effects of adiposity on systemic IT tolerance in aged compared with young obese mice. Both young ob/ob- and DIO-generated proinflammatory cytokine levels and organ pathologies are comparable to those in aged ad libitum mice after IT, culminating in lethality. Young obese mice exhibited greater ratios of M1/M2 macrophages within the peritoneal and visceral adipose tissues and higher percentages of TNF(+) macrophages in response to αCD40/IL-2 as compared with young lean mice. Macrophage depletion or TNF blockade in conjunction with αCD40/IL-2 prevented cytokine storms in young obese mice and protected from lethality. Calorie-restricted aged mice contain less visceral fat and displayed reduced cytokine levels, protection from organ pathology, and protection from lethality upon αCD40/IL-2 administration. Our data demonstrate that adiposity is a critical factor in the age-associated pathological responses to systemic anti-cancer IT.

Published
2014

17. Poor cognitive ageing: Vulnerabilities, mechanisms and the impact of nutritional interventions

Author

Miquel, Sophie, Champ, Claire, Day, Jon, Aarts, Esther, Bahr, Ben A., Bakker, Martijntje, Bánáti, Diána, Calabrese, Vittorio, Cederholm, Tommy, Cryan, John, Dye, Louise, Farrimond, Jonathan A., Korosi, Aniko, Layé, Sophie, Maudsley, Stuart, Milenkovic, Dragan, Mohajeri, M.Hasan, Sijben, John, Solomon, Alina, Spencer, Jeremy P.E., Thuret, Sandrine, Vanden Berghe, Wim, Vauzour, David, Vellas, Bruno, Wesnes, Keith, Willatts, Peter, Wittenberg, Raphael, and Geurts, Lucie

Published
2018
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20. Metal ions shape α-synuclein

Author

Moons, Rani, Konijnenberg, Albert, Mensch, Carl, Van Elzen, Roos, Johannessen, Christian, Maudsley, Stuart, Lambeir, Anne-Marie, and Sobott, Frank

Published
2020
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28. The oDGal Mouse: A Novel, Physiologically Relevant Rodent Model of Sporadic Alzheimer’s Disease

Author

Chadwick, Wayne, primary, Maudsley, Stuart, additional, Hull, William, additional, Havolli, Enes, additional, Boshoff, Eugene, additional, Hill, Mark D. W., additional, Goetghebeur, Pascal J. D., additional, Harrison, David C., additional, Nizami, Sohaib, additional, Bedford, David C., additional, Coope, Gareth, additional, Real, Katia, additional, Thiemermann, Christoph, additional, Maycox, Peter, additional, Carlton, Mark, additional, and Cole, Sarah L., additional

Published
2023
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46. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia

Author

Hardies, Katia, de Kovel, Carolien G. F., Weckhuysen, Sarah, Asselbergh, Bob, Geuens, Thomas, Deconinck, Tine, Azmi, Abdelkrim, May, Patrick, Brilstra, Eva, Becker, Felicitas, Barisic, Nina, Craiu, Dana, Braun, Kees P.J., Lal, Dennis, Thiele, Holger, Schubert, Julian, Weber, Yvonne, van ‘t Slot, Ruben, Nürnberg, Peter, Balling, Rudi, Timmerman, Vincent, Lerche, Holger, Maudsley, Stuart, Helbig, Ingo, Suls, Arvid, Koeleman, Bobby P.C., De Jonghe, Peter, Afawi, Zaid, Baulac, Stéphanie, Caglayan, Hande, Lopez, Rosa Guerrero, Guerrini, Renzo, Hjalgrim, Helle, Jähn, Johanna, Klein, Karl Martin, Leguern, Eric, Lemke, Johannes, Marini, Carla, Muhle, Hiltrud, Rosenow, Felix, Serratosa, Jose, Štěrbová, Katalin, Moller, Rikke S., Striano, Pasquale, and Zara, Federico

Published
2015
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