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Michno K, van de Hoef D, Wu H, Boulianne GL. Demented flies? usingDrosophilato model human neurodegenerative diseases.The success of biomedical research in the past few decades has led to dramatic improvements in human health and, as a result, increased life expectancy. An unexpected consequence, however, has been an increase in the number of age-related diseases and, in particular, neurodegenerative diseases. Despite their prevalence, a therapeutic void exists in part due to an incomplete understanding of the biochemical pathogenesis of these diseases. A powerful method that can be used to understand the basic mechanisms underlying neurodegenerative diseases is to generate animal models based on manipulating the expression of single genes that are disease causative. This approach has been facilitated by the fact that many neurodegenerative diseases are inherited as autosomal dominant traits such that expression of the mutant gene in a model organism might be expected to recapitulate the disease. During the past few years, the fruit fly,Drosophila melanogaster, has emerged as a powerful tool to model human neurodegenerative diseases. Here, we describe the various approaches utilized to create fly models of human neurodegenerative disease, and how they can aid in our understanding of disease pathogenesis and facilitate drug discovery and testing. [ABSTRACT FROM AUTHOR]

The acute toxicity of ammonia on Thulinius ruffoi (Bertolani, 1981), a eutardigrade isolated from a small waste water treatment plant (WWTP) in Poland, was estimated. Our results show that no active individuals survived a 24 h exposure to solutions equal to or higher than 125 mg/L of total ammonia nitrogen (NH3-N + NH4 (+)-N), which, under the conditions in our experiment, was equivalent to 1.17 mg/L of un-ionised ammonia (NH3). The LC50 concentration of total ammonia nitrogen was equal to 52 mg/L (or 0.65 mg/L un-ionised ammonia). Given that the norms for the concentration of ammonia in treated waters leaving WWTPs are usually several times lower than the LC50 for T. ruffoi, this species does not seem to be a good bioindicator candidate for WWTPs. In this paper we also note that various ecotoxicological studies use different methodological approaches and we suggest that a more uniform methodology may aid interspecific comparisons of LC50 values.

Much of our current understanding about neurodegenerative diseases can be attributed to the study of inherited forms of these disorders. For example, mutations in the presenilin 1 and 2 genes have been linked to early onset familial forms of Alzheimer's disease (FAD). Using the Drosophila central nervous system as a model we have investigated the role of presenilin in one of the earliest cellular defects associated with Alzheimer's disease, intracellular calcium deregulation. We show that expression of either wild type or FAD-mutant presenilin in Drosophila CNS neurons has no impact on resting calcium levels but does give rise to deficits in intracellular calcium stores. Furthermore, we show that a loss-of-function mutation in calmodulin, a key regulator of intracellular calcium, can suppress presenilin-induced deficits in calcium stores. Our data support a model whereby presenilin plays a role in regulating intracellular calcium stores and demonstrate that Drosophila can be used to study the link between presenilin and calcium deregulation.

Human neurodegenerative diseases are characterized by progressive neuronal cell loss often resulting in memory and cognitive decline, motor dysfunction, and ultimately premature death. Despite the prevalence of these diseases, there are no effective cures. Insight into many of these syndromes has come from the identification of single gene mutations that are associated with inherited forms of the disease. This has led to the development of animal models in which the pathogenesis caused by these genes can be rigorously examined. Due to their short life span and powerful genetic potential, several attempts have been made to model neurodegenerative diseases in the fruit fly Drosophila melanogaster. This review will describe how these models were generated and how faithfully they recapitulate human disease. In addition, how fly models can be used to identify genetic modifiers of known disease genes and what these have revealed about the biochemical pathways underlying disease pathogenesis is discussed. Finally, the review will describe how fly models can be used to identify new therapeutic targets and test the effectiveness of new drugs.

The embryonic mammary gland and hair follicle are both derived from the ventral ectoderm, and their development depends on a number of common fundamental developmental pathways. While the Hedgehog (Hh) signaling pathway is required for hair follicle morphogenesis, the role of this pathway during embryonic mammary gland development remains undetermined. We demonstrate here that, unlike the hair follicle, both Shh and Ihh are expressed in the developing embryonic mouse mammary rudiment as early as E12.5. In Shh(-/-) embryos, hair follicle development becomes arrested at an early stage, while the mammary rudiment, which continues to express Ihh, develops in a manner indistinguishable from that of wild-type littermates. The five pairs of mammary buds in Shh(-/-) female embryos exhibit normal branching morphogenesis at E16.5, forming a rudimentary ductal structure identical to wild-type embryonic mammary glands. We further demonstrate that loss of Hh signaling causes altered cyclin D1 expression in the embryonic dermal mesenchyme. Specifically, cyclin D1 is expressed at E14.5 principally in the condensed mesenchymal cells of the presumptive hair follicles and in both mesenchymal and epithelial cells of the mammary rudiments in wild-type and Shh-deficient embryos. By E18.5, robust cyclin D1 expression is maintained in mammary rudiments of both wild-type and Shh-deficient embryos. In hair follicles of wild-type embryos by E18.5, cyclin D1 expression switches to follicular epithelial cells. In contrast, strong cyclin D1 expression is observed principally in the mesenchymal cells of arrested hair follicles in Shh(-/-) embryos at E18.5. These data reveal that, despite the common embryonic origin of hair follicles and mammary glands, distinct patterns of Hh-family expression occur in these two tissues. Furthermore, these data suggest that cyclin D1 expression in the embryonic hair follicle is mediated by both Hh-independent and Hh-dependent mechanisms.