Animal Models of Coenzyme Q Deficiency: Mechanistic and Translational Learnings

Funding: This work was supported by grants from the MCIN/AEI/10.13039/501100011033, Spain, and the ERDF (RTI2018-093503-B-100); the Muscular Dystrophy Association (MDA-602322); and from the Junta de Andalucía (grant number P20_00134). P.G.-G. is ‘FPU fellow’ from the Ministerio de Universidades, Spain. A.H.-G. is supported by the “Plan Propio de Investigación” from the University of Granada. S.L.-H. is supported by the “garantía juvenil” program. E.B.-C. is supported by the Consejería de Salud, Junta de Andalucía, Spain.Coenzyme Q (CoQ) is a vital lipophilic molecule that is endogenously synthesized in the mitochondria of each cell. The CoQ biosynthetic pathway is complex and not completely characterized, and it involves at least thirteen catalytic and regulatory proteins. Once it is synthesized, CoQ exerts a wide variety of mitochondrial and extramitochondrial functions thank to its redox capacity and its lipophilicity. Thus, low levels of CoQ cause diseases with heterogeneous clinical symptoms, which are not always understood. The decreased levels of CoQ may be primary caused by defects in the CoQ biosynthetic pathway or secondarily associated with other diseases. In both cases, the pathomechanisms are related to the CoQ functions, although further experimental evidence is required to establish this association. The conventional treatment for CoQ deficiencies is the high doses of oral CoQ10 supplementation, but this therapy is not effective for some specific clinical presentations, especially in those involving the nervous system. To better understand the CoQ biosynthetic pathway, the biological functions linked to CoQ and the pathomechanisms of CoQ deficiencies, and to improve the therapeutic outcomes of this syndrome, a variety of animal models have been generated and characterized in the last decade. In this review, we show all the animal models available, remarking on the most important outcomes that each model has provided. Finally, we also comment some gaps and future research directions related to CoQ metabolism and how the current and novel animal models may help in the development of future research studies.Consejería de Salud, Junta de AndalucíaMinisterio de Universidades, SpainMuscular Dystrophy Association MDA-602322Universidad de GranadaEuropean Regional Development Fund RTI2018-093503-B-100Junta de Andalucía P20_0013

Extrapolating from Laboratory Behavioral Research on Nonhuman Primates Is Unjustified

Conducting research on animals is supposed to be valuable because it provides information on how human mechanisms work. But for the use of animal models to be ethically justified, it must be epistemically justified. The inference from an observation about an animal model to a conclusion about humans must be warranted for the use of animals to be moral. When researchers infer from animals to humans, it’s an extrapolation. Often non-human primates are used as animal models in laboratory behavioral research. The target populations are humans and other non-human primates. I argue that the epistemology of extrapolation renders the use of non-human primates in laboratory behavioral research unreliable. If the model is relevantly similar to the target, then the experimental conditions introduce confounding variables. If the model is not relevantly similar to the target, then the observations of the model cannot be extrapolated to the target. Since using non-human primates in as animal models in laboratory behavioral research is not epistemically justified, using them as animal models in laboratory behavioral research is not ethically justified

Animal models to study hepatitis C virus infection

With more than 71 million chronically infected people, the hepatitis C virus (HCV) is a major global health concern. Although new direct acting antivirals have significantly improved the rate of HCV cure, high therapy cost, potential emergence of drug-resistant viral variants, and unavailability of a protective vaccine represent challenges for complete HCV eradication. Relevant animal models are required, and additional development remains necessary, to effectively study HCV biology, virus-host interactions and for the evaluation of new antiviral approaches and prophylactic vaccines. The chimpanzee, the only non-human primate susceptible to experimental HCV infection, has been used extensively to study HCV infection, particularly to analyze the innate and adaptive immune response upon infection. However, financial, practical, and especially ethical constraints have urged the exploration of alternative small animal models. These include different types of transgenic mice, immunodeficient mice of which the liver is engrafted with human hepatocytes (humanized mice) and, more recently, immunocompetent rodents that are susceptible to infection with viruses that are closely related to HCV. In this review, we provide an overview of the currently available animal models that have proven valuable for the study of HCV, and discuss their main benefits and weaknesses

Translational animal models of autism and neurodevelopmental disorders.

Autism is a neurodevelopmental disorder whose diagnosis is based on three behavioral criteria: unusual reciprocal social interactions, deficits in communication, and stereotyped repetitive behaviors with restricted interests. A large number of de novo single gene mutations and chromosomal deletions are associated with autism spectrum disorders. Based on the strong genetic evidence, mice with targeted mutations in homologous genes have been generated as translational research tools. Mouse models of autism have revealed behavioral and biological outcomes of mutations in risk genes. The field is now poised to employ the most robust phenotypes in the most replicable mouse models for preclinical screening of novel therapeutics

Lymphoma caused by intestinal microbiota.

The intestinal microbiota and gut immune system must constantly communicate to maintain a balance between tolerance and activation: on the one hand, our immune system should protect us from pathogenic microbes and on the other hand, most of the millions of microbes in and on our body are innocuous symbionts and some can even be beneficial. Since there is such a close interaction between the immune system and the intestinal microbiota, it is not surprising that some lymphomas such as mucosal-associated lymphoid tissue (MALT) lymphoma have been shown to be caused by the presence of certain bacteria. Animal models played an important role in establishing causation and mechanism of bacteria-induced MALT lymphoma. In this review we discuss different ways that animal models have been applied to establish a link between the gut microbiota and lymphoma and how animal models have helped to elucidate mechanisms of microbiota-induced lymphoma. While there are not a plethora of studies demonstrating a connection between microbiota and lymphoma development, we believe that animal models are a system which can be exploited in the future to enhance our understanding of causation and improve prognosis and treatment of lymphoma

Animal Models of GWAS-Identified Type 2 Diabetes Genes

More than 65 loci, encoding up to 500 different genes, have been implicated by genome-wide association studies (GWAS) as conferring an increased risk of developing type 2 diabetes (T2D). Whilst mouse models have in the past been central to understanding the mechanisms through which more penetrant risk genes for T2D, for example, those responsible for neonatal or maturity-onset diabetes of the young, only a few of those identified by GWAS, notably TCF7L2 and ZnT8/SLC30A8, have to date been examined in mouse models. We discuss here the animal models available for the latter genes and provide perspectives for future, higher throughput approaches towards efficiently mining the information provided by human genetics

Animal models of Zika virus infection, pathogenesis, and immunity

Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that now causes epidemics affecting millions of people on multiple continents. The virus has received global attention because of some of its unusual epidemiological and clinical features, including persistent infection in the male reproductive tract and sexual transmission, an ability to cross the placenta during pregnancy and infect the developing fetus to cause congenital malformations, and its association with Guillain-Barré syndrome in adults. This past year has witnessed an intensive effort by the global scientific community to understand the biology of ZIKV and to develop pathogenesis models for the rapid testing of possible countermeasures. Here, we review the recent advances in and utility and limitations of newly developed mouse and nonhuman primate models of ZIKV infection and pathogenesis

Circadian Disruption and Metabolic Disease: Findings from Animal Models

Social opportunities and work demands have caused humans to become increasingly active during the late evening hours, leading to a shift from the predominantly diurnal lifestyle of our ancestors to a more nocturnal one. This voluntarily decision to stay awake long into the evening hours leads to circadian disruption at the system, tissue, and cellular levels. These derangements are in turn associated with clinical impairments in metabolic processes and physiology. The use of animal models for circadian disruption provides an important opportunity to determine mechanisms by which disorganization in the circadian system can lead to metabolic dysfunction in response to genetic, environmental, and behavioral perturbations. Here we review recent key animal studies involving circadian disruption and discuss the possible translational implications of these studies for human health and particularly for the development of metabolic disease

Validating Animal Models

This paper responds to a recent challenge for the validity of extrapolation of neurobiological knowledge from laboratory animals to humans. According to this challenge, experimental neurobiology, and thus neuroscience, is in a state of crisis because the knowledge produced in different laboratories hardly generalizes from one laboratory to another. Presumably, this is so because neurobiological laboratories use simplified animal models of human conditions that differ across laboratories. By contrast, I argue that maintaining a multiplicity of experimental protocols and simple models is well justified. It fosters rather than precludes the validity of extrapolation of neurobiological knowledge. The discipline is thriving

Validating Animal Models

Este artículo responde a un reto reciente: la validez de extrapolar el conocimiento neurobiológico del laboratorio animal a los humanos. Según esta objeción la neurobiología experimental, y por ende la neurociencia, está en crisis porque el conocimiento obtenido en los laboratorios de neurobiología utiliza modelos animales simplificados de las condiciones humanas que difieren de unos laboratorios a otros. Por el contrario, sostengo que mantener una diversidad de protocolos experimentales y de modelos simples está sobradamente justificado. Favorece, en vez de impedir, la validez de la extrapolación de conocimiento neurobiológico. La neurobiología es una disciplina floreciente.; In this paper, I respond to the challenge raised against contemporary experimental neurobiology according to which the field is in a state of crisis because of the multiple experimental protocols employed in different laboratories and strengthening their reliability that presumably preclude the validity of neurobiological knowledge. I provide an alternative account of experimentation in neurobiology which makes sense of its experimental practices. I argue that maintaining a multiplicity of experimental protocols and strengthening their reliability are well justified and they foster rather than preclude the validity of neurobiological knowledge. Thus, their presence indicates thriving rather than crisis of experimental neurobiology