Value of Invertebrate Genetics and Biology to Develop Neuroprotective and Preventive Medicine in Huntington’s Disease

During the past decade, and genetics have emerged as powerful approaches for the study of cellular responses to neurodegenerative disease proteins. Such studies have provided new strategies and rationales for the development of neuroprotective drugs, such as the pharmacological manipulation of longevity modulator networks. This chapter will describe how and why these model systems may be used as efficient translational research tools for Huntington’s disease (HD) in the discovery and development of neuroprotective drugs. Neurodegenerative diseases, including HD, constitute a large and clinically heterogeneous group of brain illnesses for which there are currently no neuroprotective drugs available. Although important methodologies have been developed by academic and industrial researchers to find therapies for these diseases, notably chemical screening tools, the large majority of the molecules so far evaluated in clinical trials have failed to show significant efficacy. In rodent models, the administration of neurotoxins may reproduce some features of the human diseases (von Bohlen Und Halbach, 2005), and this approach has been used extensively to search for new treatments with some success, such as the use of levodopa for symptomatic treatment of Parkinson’s disease, although with significant side effects (Tse, 2006). However, neuroprotective treatments able to benefit large numbers of patients with minimal side effects have not yet been developed. Thus, to date research in the field of neurodegenerative disease pathogenesis has given limited benefit to patients, and drug discovery and development remain major challenges for industrial and preindustrial research and need to be improved. Drug development is an expensive and time-consuming process that works as a pipeline, with the proof of success being conclusive clinical trials. Although there is a need to improve clinical trial design to evaluate the effects of neuroprotective drugs, improvement may also be needed at the entry points of the pipeline and at critical points along the preclinical discovery process (Hung and Schwarzschild, 2007). With the advent of physiological genomics and network biology, the concepts and paradigms used to study neurodegenerative diseases are rapidly evolving (Feany, 2000; Lim et al., 2006b). Implementing these concepts and paradigms early into the drug development process may strongly enhance the translational infrastructure used to tackle neurodegenerative diseases. The aim of this chapter is to emphasize how and why invertebrate biology may allow new rationale(s) for drug discovery and development to be exploited for the development of new drugs for HD, notably in view of developing neuroprotective and preventive medicines. HD is a dominantly inherited disease caused by expanded polyglutamines (polyQs) in the huntingtin (htt) protein (Figure 6.1) and is clinically characterized by cortical and striatal degeneration accompanied by motor, cognitive, and neuropsychiatric symptoms (Walker, 2007). The toxic effects of polyQ-expanded htt forms and genetic modifiers of cytotoxicity are being studied in several cell systems and in model organisms, including yeast, nematodes, flies, and rodents (Levine et al., 2004; Rubinsztein, 2002; Sipione and Cattaneo, 2001). Thus, a large amount of knowledge is being accumulated on the roles of normal htt and the effects of polyQ-expanded htt at the neuronal cell level. There are also great efforts being made to collect detailed clinical data in a normalized manner (e.g., see http://www.euro-hd.net) and to characterize large cohorts of HD patients and presymptomatic individuals. Thus, HD has become a “model disease” to define the best ways to fight neuronal dysfunction and neurodegeneration in the brain and to improve drug discovery, which may foster the identification of a cure for this disease and perhaps other degenerative diseases.