Molecular Targets and Therapeutic Strategies in Huntingtons Disease

Faculty of Medicine, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Current Drug Targets - CNS & Neurological Disorders 09/2005; 4(4):361-81. DOI: 10.2174/1568007054546081
Source: PubMed


This article provides an overview of the molecular mechanisms associated with striatal neuronal degeneration in Huntington's disease (HD), the most studied of the diseases caused by polyglutamine expansion. We discuss the current status of research in cellular and animal models of HD, in which protein aggregation, excitotoxicity, mitochondrial dysfunction, transcription deregulation, trophic factor starvation and the disruption of axonal transport appear to be key features for selective striatal neurodegeneration. We further emphasize some of the most promising current strategies in HD treatment. We delineate the molecular and cellular rationale underlying the development of new pharmaceutical interventions that offer new hope of future treatment for HD patients worldwide.

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    • "The capacity of glutamate to be highly toxic, yet necessary for neurotransmission, sets a fine balance between plasticity and pathology. Glutamate excitotoxicity has been implicated in a number of brain disorders, including epilepsy, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, ischemia, and trauma (Rothstein, 1996; Won et al., 2002; Hynd et al., 2004a; Tannenberg et al., 2004; Fujikawa, 2005; Rego and de Almeida, 2005; Yi and Hazell, 2006). "
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    • "The presence of neuronal intranuclear inclusions (NIIs) is a hallmark of neurodegeneration in the brains of patients with MJD (as in most other polyglutamine disorders). Since the association between polyglutamine expansions and neurodegeneration (La Spada et al., 1994), a number of mechanisms have been put forward (Aronin et al., 1999), such as altered gene transcription (reviewed in Okazawa, 2003), impairment of the cell's quality control machinery: proteasome and chaperones (reviewed in Ferrigno and Silver, 2000), and perturbation of intracellular trafficking and apoptotic cell death (Rego and de Almeida, 2005). "
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    ABSTRACT: Polyglutamine expansion diseases are inherited neurodegenerative disorders caused by the expansion of CAG repeat mutations in the coding region of genes encoding for specific proteins, mostly of unknown function. One example is Machado-Joseph disease (MJD) or spinocerebellar ataxia 3, which was described in people of Portuguese descendents and is caused by expanded ataxin-3, a polyubiquitin-binding protein. Like other neurodegenerative diseases, MJD exhibits gradual progression of symptoms that finally result in the death of the patients. Despite the identification of the genetic defects, the molecular mechanisms by which the mutant protein initiates the pathogenic process remain to be elucidated. This chapter resumes some of the most important features of polyglutamine expansion diseases with a special emphasis on MJD pathogenesis. Particular relevance is given to ataxin-3 structure and function, the formation of aggregates of mutant ataxin-3, the characteristics of current disease animal models and the most recent therapeutic strategies proposed for the treatment of MJD.
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