Therapeutic Approaches to Preventing Cell Death in Huntington Disease
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Progress in Neurobiology 99 (2012) 262–280 Contents lists available at SciVerse ScienceDirect Progress in Neurobiology jo urnal homepage: www.elsevier.com/locate/pneurobio Therapeutic approaches to preventing cell death in Huntington disease c a,b,c, Anna Kaplan , Brent R. Stockwell * a Howard Hughes Medical Institute, Columbia University, Northwest Corner Building, MC4846, 550 West 120th Street, New York, NY 10027, USA b Department of Chemistry, Columbia University, Northwest Corner Building, MC4846, 550 West 120th Street, New York, NY 10027, USA c Department of Biological Sciences, Columbia University, Northwest Corner Building, MC4846, 550 West 120th Street, New York, NY 10027, USA A R T I C L E I N F O A B S T R A C T Article history: Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the Received 1 March 2012 complexity of these diseases and our limited understanding of their pathogenesis, the design of Received in revised form 20 July 2012 therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease Accepted 17 August 2012 (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other Available online 28 August 2012 neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting Keywords: neuronal cell death pathways may slow the development of neurodegeneration. However, discovering Huntington disease small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review Cell death candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in Fragment-based drug discovery Neurodegenerative diseases HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors— fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders. ß 2012 Elsevier Ltd. All rights reserved. Contents 1. Introduction . 263 2. Huntington disease . 263 2.1. Brief history . 263 2.2. Pathology and characteristics. 263 2.3. Epidemiology . 264 2.4. Huntingtin gene . 264 2.5. Huntingtin protein . 264 2.5.1. Structure . 264 2.5.2. Function . 265 2.6. Pathogenic mechanisms in HD. 265 2.6.1. Excitotoxicity . 265 2.6.2. Mitochondrial dysfunction . 265 2.6.3. Transcriptional dysregulation . 266 2.7. Treatment . 267 2.7.1. Medication . 267 Abbreviations: HD, Huntington disease; AD, Alzheimer’s disease; PD, Parkinson’s disease; MS, multiple sclerosis; ALS, amyotrophic lateral sclerosis; FBDD, fragment-based drug discovery; HTT, huntingtin gene; Htt, huntingtin protein; CAG, cytosine-adenine-guanine; Q, glutamine; DED, death effector domain; HIP1, huntingtin interacting protein 1; NMDAR, N-methyl-D-aspartic acid receptor; EAAT2, excitatory amino-acid transporter 2; GLT1, glutamate transporter 1; DRP1, dynamin-related protein-1; PGC- 1a, peroxisome proliferator-activated receptor-g coactivator 1a; CREB, cAMP response element binding. * Corresponding author at: Howard Hughes Medical Institute, Department of Biological Sciences and Department of Chemistry, Columbia University, Northwest Corner Building, MC4846, 550 West 120th Street, New York, NY 10027, USA. Tel.: +1 212 854 2948; fax: +1 212 854 2951. E-mail address: [email protected] (B.R. Stockwell). 0301-0082/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pneurobio.2012.08.004 A. Kaplan, B.R. Stockwell / Progress in Neurobiology 99 (2012) 262–280 263 2.7.2. Non-medication therapies. 267 2.7.3. Drugs in development . 267 2.8. Summary. 269 3. Regulated cell death pathways and HD targets . 269 3.1. Apoptosis pathway . 269 3.1.1. Apoptosis in HD. 270 3.2. Pro-cell-death targets . 270 3.2.1. Caspase-1 . 270 3.2.2. Caspase-3 . 270 3.2.3. Caspase-6 . 271 3.2.4. Caspase-8 . 271 3.2.5. Caspases, all . 271 3.2.6. HIP1 . 271 3.2.7. Protein disulfide isomerase . 272 3.2.8. NMDA receptor . 272 3.2.9. DRP1. 272 3.3. Autophagy . 272 4. Drug design . 273 4.1. High-throughput screening . ..