Modeling Huntington disease in yeast: Perspectives and future directions

Yeast have been extensively used to model aspects of protein folding diseases, yielding novel mechanistic insights and identifying promising candidate therapeutic targets. In particular, the neurodegenerative disorder Huntington disease (HD), which is caused by the abnormal expansion of a polyglutamine tract in the huntingtin (htt) protein, has been widely studied in yeast. This work has led to the identification of several promising therapeutic targets and compounds that have been validated in mammalian cells, Drosophila and rodent models of HD. Here we discuss the development of yeast models of mutant htt toxicity and misfolding, as well as the mechanistic insights gleaned from this simple model. The role of yeast prions in the toxicity/misfolding of mutant htt is also highlighted. Furthermore, we provide an overview of the application of HD yeast models in both genetic and chemical screens, and the fruitful results obtained from these approaches. Finally, we discuss the future of yeast in neurodegenerative research, in the context of HD and other diseases.     

Modeling Huntington disease in Drosophila

Huntington disease (HD) is an inherited neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in the huntingtin (Htt) gene. Despite years of research, there is no treatment that extends life for patients with the disorder. Similarly, little is known about which cellular pathways that are altered by pathogenic Huntingtin (Htt) protein expression are correlated with neuronal loss. As part of a longstanding effort to gain insights into HD pathology, we have been studying the protein in the context of the fruitfly Drosophila melanogaster. We generated transgenic HD models in Drosophila by engineering flies that carry a 12-exon fragment of the human Htt gene with or without the toxic trinucleotide repeat expansion. We also created variants with a monomeric red fluorescent protein (mRFP) tag fused to Htt that allows in vivo imaging of Htt protein localization and aggregation. While wild-type Htt remains diffuse throughout the cytoplasm of cells, pathogenic Htt forms insoluble aggregates that accumulate in neuronal soma and axons. Aggregates can physically block transport of numerous organelles along the axon. We have also observed that aggregates are formed quickly, within just a few hours of mutant Htt expression. To explore mechanisms of neurodegeneration in our HD model, we performed in vivo and in vitro screens to search for modifiers of viability and pathogenic Htt aggregation. Our results identified several novel candidates for HD therapeutics that can now be tested in mammalian models of HD. Furthermore, these experiments have highlighted the complex relationship between aggregates and toxicity that exists in HD.     

Biomarkers for cardiovascular disease: challenges and future directions

The accurate diagnosis and prevention of cardiovascular disease (CVD) is an important public health goal. Although clinical characteristics such as age and gender are well-established risk factors for CVD, such features are not sufficient to identify all patients at risk. Cardiovascular biomarkers have the potential to augment clinical risk stratification by aiding in screening, diagnosis and assessment of prognosis. However, most current biomarkers have only modest predictive value, and there is a need to identify additional biomarkers from new biological pathways. The availability of platforms for profiling DNA, RNA, proteins and metabolites in clinical specimens has facilitated the 'unbiased' search for new biomarkers, which can now be tested in a clinical setting. This review highlights recent developments in the field of cardiovascular biomarkers and describes the use of new technologies for the identification of biomarkers.     

Deciphering RNA m6A regulation in aging: Perspectives on current advances and future directions

N⁶-methyladenosine (m⁶A) is a dynamic and reversible RNA modification that has emerged as a crucial player in the life cycle of RNA, thus playing a pivotal role in various biological processes. In recent years, the potential involvement of RNA m⁶A modification in aging and age-related diseases has gained increasing attention, making it a promising target for understanding the molecular mechanisms underlying aging and developing new therapeutic strategies. This Perspective article will summarize the current advances in aging-related m⁶A regulation, highlighting the most significant findings and their implications for our understanding of cellular senescence and aging, and the potential for targeting RNA m⁶A regulation as a therapeutic strategy. We will also discuss the limitations and challenges in this field and provide insights into future research directions. By providing a comprehensive overview of the current state of the field, this Perspective article aims to facilitate further advances in our understanding of the molecular mechanisms underlying aging and to identify new therapeutic targets for aging-related diseases.     

BMP signaling in congenital heart disease: new developments and future directions

Congenital heart malformations are the most common of all congenital human birth anomalies. During the past decade, research with zebrafish, chick, and mouse models have elucidated many fundamental genetic pathways that govern early cardiac patterning and differentiation. This review highlights the roles of the bone morphogenetic protein (BMP) signaling pathway in cardiogenesis and how defective BMP signals can disrupt the intricate steps of cardiac formation and cause congenital heart defects.     

Huntington disease: genetics and epidemiology

Huntington disease (HD) is an autosomal dominant disorder in which the major gene expression occurs in the central nervous system. It is characterized by the appearance of progressive chorea and dementia, usually in adult life. One tragic aspect of the disorder, due to its late age of onset and, until recently, lack of a presymptomatic marker, is that transmission of the disease to offspring invariably occurs before symptoms develop in the parent. Although the onset of symptoms and the rate of progression may vary, the prognosis is one of relentless deterioration. The major pathological features of HD are a primary loss of cells in the caudate nucleus and putamen (striatum) but other regions of the basal ganglia, hypothalamus, and brain stem are also involved. Not only is there neuronal loss but there is also a decrease in the level of a number of neurotransmitters and associated enzymes, together with abnormalities in some receptor sites. Martin [1] described the disease as "genetically programmed cell death in the human central nervous system."     

Aromatase inhibitors: future directions

Estrogen and its cognate estrogen receptor are key players in the etiology and progression of breast cancer. Aromatase inhibitors, suppressing tumor and plasma estrogen levels by blocking testosterone conversion to estrogen, have been proven to provide the most effective endocrine therapy for postmenopausal breast cancer patients. Aromatase inhibitors are now the first choice endocrine therapy in the metastatic setting for postmenopausal women. These endocrine agents also seem likely to soon become the standard adjuvant therapy, either alone or in sequence with tamoxifen, though their long-term toxicity and the optimum duration of therapy still remain to be defined. Advanced experimental studies and some clinical observations reveal the importance of blocking both the genomic and non-genomic activities of the estrogen receptor, as well as its crosstalk with growth factor and other cellular signaling, for greatest effectiveness of endocrine therapy. Consequently, these studies provide a mechanistic explanation for the superb performance of aromatase inhibitors, and also suggest how inhibiting selected growth factor receptors might delay or prevent the onset of resistance to aromatase inhibitors and other endocrine therapies.     

Amphibian declines: future directions

Abstract. The amphibian decline problem is complex, and there is no easy solution. I highlight four major areas of future research that should increase our ability to detect declines, elucidate their underlying mechanisms, and advance our capacity to manage and conserve amphibian populations. First, a statistically sensitive monitoring approach is necessary to determine the distribution and abundance of amphibian populations, to assess whether they are declining, and to quantify the extent of declines. Most amphibian populations characteristically fluctuate, detection probabilities may be low for many species and populations tend to decline in numbers between years more often than they increase. These traits make establishing monitoring programmes difficult and distinguishing declines from natural fluctuations challenging. It is thus necessary to determine the best monitoring techniques based on their statistical power and to use appropriate statistical methods for detecting population trends. Secondly, although amphibian population studies occur most commonly at single or few breeding sites, research should occur often at the landscape level, and conservation efforts should focus on suitable habitat (whether or not it is occupied) and dispersal capabilities of species. Metapopulation dynamics are probably important for many species, but we must be cautious how we define metapopulations. That is, the term ‘metapopulation’ is currently used to define a wide range of demographic situations in amphibian populations, each with different management implications. Thirdly, recent advances in molecular genetic techniques make it possible to infer demographic events such as effects of recent fragmentation, bottlenecks or hybridization. Molecular techniques can be used in conjunction with census surveys to bolster knowledge about demographic processes such as declines. Alternatively, in the absence of long‐term census data, molecular data can be used to infer population trends. New genomic approaches may make estimating adaptive genetic variation more feasible. Fourthly, multi‐factorial studies are needed to disentangle the complexity of the several putative causes that probably interact to cause amphibian declines. Recent studies demonstrate the value of a multi‐factorial approach, and more work is needed to elucidate the synergistic effects of multiple environmental factors affecting amphibian populations simultaneously worldwide.     

Habitat complexity: approaches and future directions

Habitat complexity is one of the most important factors structuring biotic assemblages, yet we still lack basic understanding of the underlying mechanisms. Although it is one of the primary targets in conservation management, no methods are available for comparing complexity across ecosystems, and system-specific qualitative assessment predominates. Despite its overwhelming importance for faunal diversity and abundance, there has been surprisingly little interest in examining its effects on other community and ecosystem attributes. We discuss possibilities of such effects, outlining potentially fruitful areas for future research, and argue that complexity may be implicated in community persistence and ecosystem stability by acting as a decoupling mechanism in predator–prey interactions. We provide a brief overview of methods used to quantify complexity in different ecosystems, highlighting contributions of the current issue of Hydrobiologia, and discuss potential application of these approaches for cross-ecosystem comparisons. Better understanding of the role of habitat complexity resulting from such comparisons is critically important for preservation of biodiversity and ecosystem function in an era of unprecedented habitat loss.     

Catumaxomab: Clinical development and future directions

Catumaxomab, a monoclonal bispecific trifunctional antibody, was approved in the european Union in April 2009 for the intraperitoneal treatment of patients with malignant ascites. The marketing authorization holder Fresenius Biotech GmbH developed catumaxomab (Removab^®) together with its partner TRiOn Pharma GmbH, Germany. it is the first substance worldwide with a regulatory label for the treatment of malignant ascites due to epithelial carcinomas. Since the peritoneum is of mesothelial origin and therefore lacks epCAM expression, the intraperitoneal administration of catumaxomab is an attractive targeted immunotherapeutic approach. Catumaxomab is able to destroy epCAM positive tumor cells in the peritoneal cavity known as the main cause of malignant ascites. in addition, catumaxomab is a potential therapeutic option for several primary tumors since the epCAM molecule is expressed on the majority of epithelial carcinomas. This review focuses on the clinical development of catumaxomab and indicates future directions.Key words: catumaxomab, Removab^®, monoclonal antibody, trifunctional, EpCAM, malignant ascites, peritoneal carcinomatosis, immunotherapy     

Bio-ontologies: current trends and future directions

In recent years, as a knowledge-based discipline, bioinformatics has been made more computationally amenable. After its beginnings as a technology advocated by computer scientists to overcome problems of heterogeneity, ontology has been taken up by biologists themselves as a means to consistently annotate features from genotype to phenotype. In medical informatics, artifacts called ontologies have been used for a longer period of time to produce controlled lexicons for coding schemes. In this article, we review the current position in ontologies and how they have become institutionalized within biomedicine. As the field has matured, the much older philosophical aspects of ontology have come into play. With this and the institutionalization of ontology has come greater formality. We review this trend and what benefits it might bring to ontologies and their use within biomedicine.     

White matter integrity and vulnerability to Alzheimer's disease: Preliminary findings and future directions

Neuroimaging biomarkers that precede cognitive decline have the potential to aid early diagnosis of Alzheimer's disease (AD). A body of diffusion tensor imaging (DTI) work has demonstrated declines in white matter (WM) microstructure in AD and its typical prodromal state, amnestic mild cognitive impairment. The present review summarizes recent evidence suggesting that WM integrity declines are present in individuals at high AD-risk, prior to cognitive decline. The available data suggest that AD-risk is associated with WM integrity declines in a subset of tracts showing decline in symptomatic AD. Specifically, AD-risk has been associated with WM integrity declines in tracts that connect gray matter structures associated with memory function. These tracts include parahippocampal WM, the cingulum, the inferior fronto-occipital fasciculus, and the splenium of the corpus callosum. Preliminary evidence suggests that some AD-risk declines are characterized by increases of radial diffusivity, raising the possibility that a myelin-related pathology may contribute to AD onset. These findings justify future research aimed at a more complete understanding of the neurobiological bases of DTI-based declines in AD. With continued refinement of imaging methods, DTI holds promise as a method to aid identification of presymptomatic AD. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Biomarkers of lymphatic function and disease: state of the art and future directions

Substantial advances have accrued over the last decade in the identification of the processes that contribute to lymphatic vascular development in health and disease. Identification of distinct regulatory milestones, from a variety of genetic models, has led to a stepwise chronology of lymphatic development. Several molecular species have been identified as important tissue biomarkers of lymphatic development and function. At present, vascular endothelial growth-factor receptor (VEGFR)-3/VEGF-C/VEGF-D signaling has proven useful in the identification of clinical lymphatic metastatic potential and the assessment of cancer prognosis. Similar biomarkers, to be utilized as surrogates for the assessment of inherited and acquired diseases of the lymphatic circulation, are actively sought, and will represent a signal advance in biomedical investigation.     

White matter integrity and vulnerability to Alzheimer's disease: preliminary findings and future directions

Neuroimaging biomarkers that precede cognitive decline have the potential to aid early diagnosis of Alzheimer's disease (AD). A body of diffusion tensor imaging (DTI) work has demonstrated declines in white matter (WM) microstructure in AD and its typical prodromal state, amnestic mild cognitive impairment. The present review summarizes recent evidence suggesting that WM integrity declines are present in individuals at high AD-risk, prior to cognitive decline. The available data suggest that AD-risk is associated with WM integrity declines in a subset of tracts showing decline in symptomatic AD. Specifically, AD-risk has been associated with WM integrity declines in tracts that connect gray matter structures associated with memory function. These tracts include parahippocampal WM, the cingulum, the inferior fronto-occipital fasciculus, and the splenium of the corpus callosum. Preliminary evidence suggests that some AD-risk declines are characterized by increases of radial diffusivity, raising the possibility that a myelin-related pathology may contribute to AD onset. These findings justify future research aimed at a more complete understanding of the neurobiological bases of DTI-based declines in AD. With continued refinement of imaging methods, DTI holds promise as a method to aid identification of presymptomatic AD. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Veterinary parasitic vaccines: pitfalls and future directions

Most available antiparasitic drugs are safe, cheap and highly effective against a broad spectrum of parasites. However, the alarming increase in the number of parasite species that are resistant to these drugs, the issue of residues in the food chain and the lack of new drugs stimulate development of alternative control methods in which vaccines would have a central role. Parasite vaccines are still rare, but there are encouraging signs that their number will increase in the next decade. The modern paradigm is that an understanding of parasite genes will lead to the identification of useful antigens, which can then be produced in recombinant systems developed as a result of the huge investment in biotechnology. However, we should also continue to devote efforts to basic research on the host-parasite interface.