The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies

Expansion of CAG trinucleotide repeat within the coding region of several genes results in the production of proteins with expanded polyglutamine (PolyQ) stretch. The expression of these pathogenic proteins leads to PolyQ diseases, such as Huntington's disease or several types of spinocerebellar ataxias. This family of neurodegenerative disorders is characterized by constant progression of the symptoms and molecularly, by the accumulation of mutant proteins inside neurons causing their dysfunction and eventually death. So far, no effective therapy actually preventing the physical and/or mental decline has been developed. Experimental therapeutic strategies either target the levels or processing of mutant proteins in an attempt to prevent cellular deterioration, or they are aimed at the downstream pathologic effects to reverse or ameliorate the caused damages. Certain pathomechanistic aspects of PolyQ disorders are discussed here. Relevance of disease models and recent knowledge of therapeutic possibilities is reviewed and updated.     

Animal models of regenerative medicine for biological treatment approaches of degenerative disc diseases

Degenerative disc disease (DDD) is a painful, chronic and progressive disease, which is characterized by inflammation, structural and biological deterioration of the intervertebral disc (IVD) tissues. DDD is specified as cell-, age-, and genetic-dependent degenerative process that can be accelerated by environmental factors. It is one of the major causes of chronic back pain and disability affecting millions of people globally. Current treatment options, such as physical rehabilitation, pain management, and surgical intervention, can provide only temporary pain relief. Different animal models have been used to study the process of IVD degeneration and develop therapeutic options that may restore the structure and function of degenerative discs. Several research works have depicted considerable progress in understanding the biological basis of disc degeneration and the therapeutic potentials of cell transplantation, gene therapy, applications of supporting biomaterials and bioactive factors, or a combination thereof. Since animal models play increasingly significant roles in treatment approaches of DDD, we conducted an electronic database search on Medline through June 2020 to identify, compare, and discuss publications regarding biological therapeutic approaches of DDD that based on intradiscal treatment strategies. We provide an up-to-date overview of biological treatment strategies in animal models including mouse, rat, rabbit, porcine, bovine, ovine, caprine, canine, and primate models. Although no animal model could profoundly reproduce the clinical conditions in humans; animal models have played important roles in specifying our knowledge about the pathophysiology of DDD. They are crucial for developing new therapy approaches for clinical applications.     

Protein-misfolding diseases and chaperone-based therapeutic approaches

A large number of neurodegenerative diseases in humans result from protein misfolding and aggregation. Protein misfolding is believed to be the primary cause of Alzheimer's disease, Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease, cystic fibrosis, Gaucher's disease and many other degenerative and neurodegenerative disorders. Cellular molecular chaperones, which are ubiquitous, stress-induced proteins, and newly found chemical and pharmacological chaperones have been found to be effective in preventing misfolding of different disease-causing proteins, essentially reducing the severity of several neurodegenerative disorders and many other protein-misfolding diseases. In this review, we discuss the probable mechanisms of several protein-misfolding diseases in humans, as well as therapeutic approaches for countering them. The role of molecular, chemical and pharmacological chaperones in suppressing the effect of protein misfolding-induced consequences in humans is explained in detail. Functional aspects of the different types of chaperones suggest their uses as potential therapeutic agents against different types of degenerative diseases, including neurodegenerative disorders.     

人类疾病的动物模型

发展对人类疾病有效的预测、预防、诊断和治疗等途径,一直是人口健康领域关注的焦点.任何人类疾病似乎都可归咎于遗传背景和环境因素的共同作用,并影响到疾病的发生、病程、药物疗效和预后等.最有效的研究策略足直接针对患者的各方面临床研究,但这一策略常常会而临着同一临床症状却有不同病因(异质性)、个体差异显著(如治疗效果因人而异)以及难以回溯性地研究人类疾病的发生、发展(如发病以前的事件或经历)等问题,而且医学伦理学的要求使得大量医学研究和新药新疗法不能直接应用于人体,必须先有动物实验阐明其安全性和必要性.最佳的研究策略足创建人类疾病的动物模型,因为可严格地控制病因、遗传背景、环境因子等,也可跟踪性研究动物模型病症的发生、发展、治疗反应和结局等,但这一策略也常常面临着一系列问题和误解.对此,在<动物学研究>出版<灵长类动物与人类疾病模型>专刊之际,撰写此评述性论文,将系列问题和误解一一提出,并讨论其应对策略.     

Animal models of neurodegenerative diseases

Numerous evidences indicate that the phenotype of a neurodegenerative disease and its pathogenetic mechanism are only loosely linked. The phenotype is directly related to the topography of the lesions and is reproduced whatever the mechanism as soon as the same neurons are destroyed or deficient: the symptoms of Parkinson disease are mimicked by any destruction of the neurons of the substantia nigra, caused for instance by the toxin MPTP. This does not mean that idiopathic Parkinson disease is due to MPTP. In the same way, mouse lines such as Reeler, Weaver and Staggerer in which ataxia occurs spontaneously does not help to understand human ataxias: now that mutations responsible for these phenotypes have been identified, it appears that one is responsible for lissencephaly (mutation of the reelin gene) and the other two have no equivalent in man. Therapeutic attempts, however, rely on the understanding of the pathogenetic mechanisms. Introducing a mutated human transgene in the genome of an animal has, in many instances, significantly improved this understanding. Transgenic mice have proven useful in reproducing lesions seen in neurodegenerative disease such as the plaques of Alzheimer disease (in the APP mouse which has integrated the mutated gene of the amyloid protein precursor), the tau glial and neuronal accumulation (seen in cases of frontotemporal dementias due to tau mutation), the nuclear inclusions caused by CAG triplet expansion (seen in the mutation of Huntington disease and autosomal dominant spinocerebellar ataxias). These recent advances have fostered numerous therapeutic attempts. Transgenesis in drosophila and in the worm Caenorhabditis elegans have opened new possibilities in the screening of protein partners, modifier genes, and potential therapeutic molecules. However, it is also becoming clear that introducing a human mutated gene in an animal does not necessarily trigger pathogenetic cascades identical to those seen in the human disease. Human diseases have to be studied in parallel with their animal models to ensure that the model mimic at least a few original mechanisms, on which new therapeutics may be tested.     

Animal models of primary myocardial diseases

Feline and canine cardiomyopathies (primary myocardial diseases) were reviewed and divided into three groups based on the clinical, hemodynamic, angiocardiographic, and pathologic findings: (1) feline and canine hypertrophic cardiomyopathy, (2) feline and canine congestive (dilated) cardiomyopathy, and (3) feline restrictive cardiomyopathy. All three groups consisted predominantly of mature adult male cats and dogs. Cardiomyopathy in the hamster and turkey was also reviewed. The most common presenting signs were dyspnea and/or thromboembolism in the cat, systolic murmurs with gallop rhythms on auscultation, cardiomegaly with (groups 1 and 3) or without (group 2) pulmonary edema, abnormal electrocardiograms, elevated left ventricular end-diastolic pressures, and angiocardiographic evidence of mitral regurgitation with left ventricular concentric hypertrophy (group 1), left ventricular dilatation (group 2), or midventricular stenosis (group 3). Some cats in groups 1 and 3 also had evidence of left ventricular outflow obstruction. The principal pathologic findings in all of the cats and dogs were left atrial dilation, hypertrophy, increased septal:left ventricular free wall thickness ratio with disorganization of cardiac muscle cells (group 1); dilatation of the four chambers with degeneration of cardiac muscle cells (group 2); and extensive endocardial fibrosis and adhesion of the left ventricle (group 3). Aortic thromboembolism was commonly observed in the cats of all three groups. These clinical and pathologic findings indicate that cardiomyopathy in the cat or dog is similar to the three forms of cardiomyopathy in humans (hypertrophic, congestive, and restrictive).     

Animal models of HLA-B27-associated diseases

The HLA-B27 molecule is strongly associated with the spondyloarthropathies (SpA), a group of inflammatory conditions affecting the skeleton, the skin and several mucosae. The mechanism of this association remains unknown, largely because the HLA-B27 molecule displays normal function. A disease that closely mimicks SpA arises spontaneously in HLA-B27 transgenic rats. This disease is dependent on the presence of a normal bacterial flora and implicates the immune system. The presence of both CD4+ T cells and antigen presenting cells (APCs) expressing high levels of HLA-B27, seems of critical importance in its pathogenesis, whereas CD8+ T cells are dispensable. The T cell stimulatory function of APCs is disturbed by the HLA-B27 molecule. This disease could result from a failure of tolerance, related in part to high level of B27 expression in professional APCs and to the immune response to gut bacteria. In contrast, HLA-B27 transgenic mice have usually remained healthy. However, two types of inflammatory conditions affecting the skeleton, which arise in mice of susceptible background after exposure to a conventional bacterial flora, are increased by an HLA-B27 transgene. The first is ANKENT, a spontaneous ankylosing enthesitis that affects ankle and/or tarsal joints of ageing mice; the second is a spontaneous arthritis of hindpaws developing in mice lacking endogenous mbeta2m. As in rats, the absence of CD8+ T cells in the latter model, argues against the "arthritogenic peptide" hypothesis. In these mbeta2m0 mice, B27 free heavy chain could be implicated in the pathogenesis of arthritis by presenting extracellular peptides to CD4+ T cells.     

Enhanced SUMOylation in polyglutamine diseases

Small ubiquitin-like modifiers (SUMOs) are proteins homologous to ubiquitin that possibly regulate intranuclear protein localization, nuclear transport, and ubiquitination. We examined patients of DRPLA, SCA1, MJD, and Huntington's disease and found that neurons in affected regions of the brain react strongly to SUMO-1, a family member of SUMOs. Western blot with a transgenic mouse expressing mutant ataxin-1 showed the increase of SUMOylated proteins in the cerebellar cortex, which we named ESCA1 and ESCA2. These results indicated activation of SUMO-1 system in polyglutamine diseases and predicted its involvement in the pathology.     

Cell death in polyglutamine diseases

An increasing number of inherited neurodegenerative diseases are known to be caused by trinucleotide repeat expansions in the respective genes. At least nine disorders result from a CAG trinucleotide repeat expansion which is translated into a polyglutamine stretch in the respective proteins: Huntington's disease (HD), dentatorubral pallidolysian atrophy (DRPLA), spinal bulbar muscular atrophy (SBMA), and several of the spinocerebellar ataxias (SCA1, 2, 3, 6, 7 and 12). Although the molecular steps leading to the specific neuropathology of each disease are unknown and are still under intensive investigation, there is increasing evidence that some CAG repeat disorders involve the induction of apoptotic mechanisms. This review summarizes the clinical and genetic features of each CAG repeat disorder and focuses on the common mechanistic steps involved in the disease progression of these so-called polyglutamine diseases. Among the common molecular features the formation of intranuclear inclusions, the recruitment of interacting polyglutamine-containing proteins, the involvement of the proteasome and molecular chaperones, and the activation of caspases are discussed with regard to their potential implication for the induction of cell death.     

Animal models of complex diseases: an initial strategy

We speculated that the rise in atmospheric oxygen from 2 billion years ago was so integral for the evolution of biocomplexity that it must also associate strongly with complex diseases. As a remote test of this idea, we hypothesized that lines contrasting for disease and health would emerge from artificial selection for low and high aerobic treadmill running capacity. Eleven generations of selection in rats produced lines that differed by 347% in running capacity. The low line demonstrated health risk factors including higher visceral adiposity, blood pressure, insulin, and triglycerides. The high line was superior for VO2max, economy of running, heart function, and nitric oxide-induced vascular dilation.     

Animal models of oxidative stress,aging, and therapeutic antioxidant interventions

Oxidative stress is a ubiquitous phenomena in all cell types, and it is primarily produced in mitochondria which are essential for multicellular life. Oxidative stress targets can be wide ranging and include nucleic acids and a variety of macromolecules. This review discusses the role of oxidative stress in the context of animal models, focusing in particular on animal models of aging, as well as the development of a new class of therapeutic small molecular weight antioxidants that have proven effective in extending the lifespan of a simple invertebrate nematode.     

Designing improved active peptides for therapeutic approaches against infectious diseases

Infectious diseases are one of the main causes of human morbidity and mortality. In the last few decades, pathogenic microorganisms' resistance to conventional drugs has been increasing, and it is now pinpointed as a major worldwide health concern. The need to search for new therapeutic options, as well as improved treatment outcomes, has therefore increased significantly, with biologically active peptides representing a new alternative. A substantial research effort is being dedicated towards their development, especially due to improved biocompatibility and target selectivity. However, the inherent limitations of peptide drugs are restricting their application. In this review, we summarize the current status of peptide drug development, focusing on antiviral and antimicrobial peptide activities, highlighting the design improvements needed, and those already being used, to overcome the drawbacks of the therapeutic application of biologically active peptides.