Mitochondrial targeting of XJB-5-131 attenuates or improves pathophysiology in HdhQ150 animals with well-developed disease phenotypes

Polyzos, Aris; Holt, Amy; Brown, Christopher; Cosme, Celica; Wipf, Peter; Gomez-Marin, Alex; Castro, Maríadel R.; Ayala-Peña, Sylvette; McMurray, Cynthia T.

doi:10.1093/hmg/ddw051

Title: Mitochondrial targeting of XJB-5-131 attenuates or improves pathophysiology in HdhQ150 animals with well-developed disease phenotypes

Journal Article · 20 February 2016 · Human Molecular Genetics

DOI: https://doi.org/10.1093/hmg/ddw051 · OSTI ID:1379313

Polyzos, Aris ^[1]; Holt, Amy ^[1]; Brown, Christopher ^[2]; Cosme, Celica ^[2]; Wipf, Peter ^[3]; Gomez-Marin, Alex ^[4]; Castro, Maríadel R. ^[5]; Ayala-Peña, Sylvette ^[5]; McMurray, Cynthia T. ^[1]

Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Univ. of California, Berkeley, CA (United States)
Univ. of Pittsburgh, PA (United States)
Consejo Superior de Investigaciones Cientificas (CSIC), Madrid (Spain)
Univ. of Puerto Rico, San Juan, PR (United States)

Oxidative damage to mitochondria (MT) is a major mechanism for aging and neurodegeneration. We have developed a novel synthetic antioxidant, XJB-5-131, which directly targets MT, the primary site and primary target of oxidative damage. XJB-5-131 prevents the onset of motor decline in an HdhQ(150/150) mouse model for Huntington's disease (HD) if treatment starts early. Here, we report that XJB-5-131 attenuates or reverses disease progression if treatment occurs after disease onset. In animals with well-developed pathology, XJB-5-131 promotes weight gain, prevents neuronal death, reduces oxidative damage in neurons, suppresses the decline of motor performance or improves it, and reduces a graying phenotype in treated HdhQ(150/150) animals relative to matched littermate controls. XJB-5-131 holds promise as a clinical candidate for the treatment of HD.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: National Institutes of Health; USDOE

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1379313

Journal Information:: Human Molecular Genetics, Journal Name: Human Molecular Genetics Journal Issue: 9 Vol. 25; ISSN 0964-6906

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

References (51)

Current and Future Public Health Challenges Koplan, Jeffrey P. JAMA, Vol. 284, Issue 13 https://doi.org/10.1001/jama.284.13.1696	journal	October 2000
A Randomized Clinical Trial of High-Dosage Coenzyme Q10 in Early Parkinson Disease: No Evidence of Benefit Beal, M. Flint; Oakes, David; Shoulson, Ira JAMA Neurology, Vol. 71, Issue 5 https://doi.org/10.1001/jamaneurol.2014.131	journal	May 2014
A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease Snow, Barry J.; Rolfe, Fiona L.; Lockhart, Michelle M. Movement Disorders, Vol. 25, Issue 11 https://doi.org/10.1002/mds.23148	journal	June 2010
Therapeutic advances in Huntington's Disease: Therapeutic Advances in HD Shannon, Kathleen M.; Fraint, Avram Movement Disorders, Vol. 30, Issue 11 https://doi.org/10.1002/mds.26331	journal	July 2015
Analysis of Gene-Specific DNA Damage and Repair Using Quantitative Polymerase Chain Reaction Ayala-Torres, Sylvette; Chen, Yiminig; Svoboda, Tamara Methods, Vol. 22, Issue 2 https://doi.org/10.1006/meth.2000.1054	journal	October 2000
Creatine Increases Survival and Delays Motor Symptoms in a Transgenic Animal Model of Huntington's Disease Andreassen, Ole A.; Dedeoglu, Alpaslan; Ferrante, Robert J. Neurobiology of Disease, Vol. 8, Issue 3 https://doi.org/10.1006/nbdi.2001.0406	journal	June 2001
Transcription, Epigenetics and Ameliorative Strategies in Huntington’s Disease: a Genome-Wide Perspective Valor, Luis M. Molecular Neurobiology, Vol. 51, Issue 1 https://doi.org/10.1007/s12035-014-8715-8	journal	May 2014
Effects of coenzyme Q10 administration on its tissue concentrations, mitochondrial oxidant generation, and oxidative stress in the rat Kwong, Linda K.; Kamzalov, Sergey; Rebrin, Igor Free Radical Biology and Medicine, Vol. 33, Issue 5 https://doi.org/10.1016/S0891-5849(02)00916-4	journal	September 2002
Oral Coenzyme Q10 Supplementation in Patients with Nonalcoholic Fatty Liver Disease: Effects on Serum Vaspin, Chemerin, Pentraxin 3, Insulin Resistance and Oxidative Stress Farhangi, Mahdieh Abbasalizad; Alipour, Beytollah; Jafarvand, Elnaz Archives of Medical Research, Vol. 45, Issue 7 https://doi.org/10.1016/j.arcmed.2014.11.001	journal	October 2014
Antioxidants in Huntington's disease Johri, Ashu; Beal, M. Flint Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Vol. 1822, Issue 5 https://doi.org/10.1016/j.bbadis.2011.11.014	journal	May 2012
Alzheimer Mechanisms and Therapeutic Strategies Huang, Yadong; Mucke, Lennart Cell, Vol. 148, Issue 6 https://doi.org/10.1016/j.cell.2012.02.040	journal	March 2012
Targeting of XJB-5-131 to Mitochondria Suppresses Oxidative DNA Damage and Motor Decline in a Mouse Model of Huntington’s Disease Xun, Zhiyin; Rivera-Sánchez, Sulay; Ayala-Peña, Sylvette Cell Reports, Vol. 2, Issue 5 https://doi.org/10.1016/j.celrep.2012.10.001	journal	November 2012
Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1α in Huntington's disease neurodegeneration Weydt, Patrick; Pineda, Victor V.; Torrence, Anne E. Cell Metabolism, Vol. 4, Issue 5 https://doi.org/10.1016/j.cmet.2006.10.004	journal	November 2006
Environmental, pharmacological, and genetic modulation of the HD phenotype in transgenic mice Schilling, Gabriele; Savonenko, Alena V.; Coonfield, Michael L. Experimental Neurology, Vol. 187, Issue 1 https://doi.org/10.1016/j.expneurol.2004.01.003	journal	May 2004
Mitochondrial DNA damage Is associated with reduced mitochondrial bioenergetics in Huntington's disease Siddiqui, Almas; Rivera-Sánchez, Sulay; Castro, María del R. Free Radical Biology and Medicine, Vol. 53, Issue 7 https://doi.org/10.1016/j.freeradbiomed.2012.06.008	journal	October 2012
Mitochondrial Diseases of the Brain Chaturvedi, Rajnish K.; Flint Beal, M. Free Radical Biology and Medicine, Vol. 63 https://doi.org/10.1016/j.freeradbiomed.2013.03.018	journal	October 2013
Evaluation of cytotoxicity of oils used in coenzyme Q10 Self-Emulsifying Drug Delivery Systems (SEDDS) Palamakula, Anitha; Khan, Mansoor A. International Journal of Pharmaceutics, Vol. 273, Issue 1-2 https://doi.org/10.1016/j.ijpharm.2003.12.010	journal	April 2004
Coenzyme Q, oxidative stress and aging Sohal, Rajindar S.; Forster, Michael J. Mitochondrion, Vol. 7 https://doi.org/10.1016/j.mito.2007.03.006	journal	June 2007
Formation and repair of oxidative damage in the mitochondrial DNA Muftuoglu, Meltem; Mori, Mateus P.; Souza-Pinto, Nadja C. de Mitochondrion, Vol. 17 https://doi.org/10.1016/j.mito.2014.03.007	journal	July 2014
Huntington's disease knock-in male mice show specific anxiety-like behaviour and altered neuronal maturation Orvoen, Sophie; Pla, Patrick; Gardier, Alain M. Neuroscience Letters, Vol. 507, Issue 2 https://doi.org/10.1016/j.neulet.2011.11.063	journal	January 2012
Sustained Therapeutic Reversal of Huntington's Disease by Transient Repression of Huntingtin Synthesis Kordasiewicz, Holly B.; Stanek, Lisa M.; Wancewicz, Edward V. Neuron, Vol. 74, Issue 6 https://doi.org/10.1016/j.neuron.2012.05.009	journal	June 2012
Clinical aspects of coenzyme Q10: An update Littarru, Gian Paolo; Tiano, Luca Nutrition, Vol. 26, Issue 3 https://doi.org/10.1016/j.nut.2009.08.008	journal	March 2010
Mitochondria-targeted ROS scavenger improves post-ischemic recovery of cardiac function and attenuates mitochondrial abnormalities in aged rats Escobales, Nelson; Nuñez, Rebeca E.; Jang, Sehwan Journal of Molecular and Cellular Cardiology, Vol. 77 https://doi.org/10.1016/j.yjmcc.2014.10.009	journal	December 2014
Targeting Mitochondria Hoye, Adam T.; Davoren, Jennifer E.; Wipf, Peter Accounts of Chemical Research, Vol. 41, Issue 1 https://doi.org/10.1021/ar700135m	journal	January 2008
Superoxide Dismutases and Superoxide Reductases Sheng, Yuewei; Abreu, Isabel A.; Cabelli, Diane E. Chemical Reviews, Vol. 114, Issue 7 https://doi.org/10.1021/cr4005296	journal	January 2014
Mitochondrial Targeting of Selective Electron Scavengers: Synthesis and Biological Analysis of Hemigramicidin−TEMPO Conjugates Wipf, Peter; Xiao, Jingbo; Jiang, Jianfei Journal of the American Chemical Society, Vol. 127, Issue 36 https://doi.org/10.1021/ja053679l	journal	September 2005
Allylic Amines as Key Building Blocks in the Synthesis of ( E )-Alkene Peptide Isosteres Skoda, Erin M.; Davis, Gary C.; Wipf, Peter Organic Process Research & Development, Vol. 16, Issue 1 https://doi.org/10.1021/op2002613	journal	November 2011
Characterization of Hydantoin Products from One-Electron Oxidation of 8-Oxo-7,8-dihydroguanosine in a Nucleoside Model Luo, Wenchen; Muller, James G.; Rachlin, Elliot M. Chemical Research in Toxicology, Vol. 14, Issue 7 https://doi.org/10.1021/tx010072j	journal	July 2001
Pivotal Role for Two Electron Reduction in 2,3-Dimethoxy-1,4-naphthoquinone and 2-Methyl-1,4-naphthoquinone Metabolism and Kinetics in Vivo That Prevents Liver Redox Stress Parry, Joel D.; Pointon, Amy V.; Lutz, Ursula Chemical Research in Toxicology, Vol. 22, Issue 4 https://doi.org/10.1021/tx800472z	journal	April 2009
Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences: Mitochondrial dysfunction in Parkinson's disease Exner, Nicole; Lutz, Anne Kathrin; Haass, Christian The EMBO Journal, Vol. 31, Issue 14 https://doi.org/10.1038/emboj.2012.170	journal	June 2012
Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity Song, Wenjun; Chen, Jin; Petrilli, Alejandra Nature Medicine, Vol. 17, Issue 3 https://doi.org/10.1038/nm.2313	journal	February 2011
NIH Image to ImageJ: 25 years of image analysis Schneider, Caroline A.; Rasband, Wayne S.; Eliceiri, Kevin W. Nature Methods, Vol. 9, Issue 7 https://doi.org/10.1038/nmeth.2089	journal	June 2012
Lipidomics identifies cardiolipin oxidation as a mitochondrial target for redox therapy of brain injury Ji, Jing; Kline, Anthony E.; Amoscato, Andrew Nature Neuroscience, Vol. 15, Issue 10 https://doi.org/10.1038/nn.3195	journal	August 2012
Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington's disease transgenic mice: Creatine therapy in Huntington's disease Dedeoglu, Alpaslan; Kubilus, James K.; Yang, Lichuan Journal of Neurochemistry, Vol. 85, Issue 6 https://doi.org/10.1046/j.1471-4159.2003.01706.x	journal	April 2003
Neurological abnormalities in a knock-in mouse model of Huntington's disease Lin, C. -H. Human Molecular Genetics, Vol. 10, Issue 2 https://doi.org/10.1093/hmg/10.2.137	journal	January 2001
Mitochondria‐targeted antioxidants protect Friedreich Ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants Jauslin, Matthias L.; Meier, Thomas; Smith, Robin A. J. The FASEB Journal, Vol. 17, Issue 13 https://doi.org/10.1096/fj.03-0240fje	journal	August 2003
Mitochondria‐targeted antioxidants Oyewole, Anne O.; Birch‐Machin, Mark A. The FASEB Journal, Vol. 29, Issue 12 https://doi.org/10.1096/fj.15-275404	journal	August 2015
Neuropathological Classification of Huntingtonʼs Disease Vonsattel, Jean-Paul; Myers, Richard H.; Stevens, Thomas J. Journal of Neuropathology and Experimental Neurology, Vol. 44, Issue 6 https://doi.org/10.1097/00005072-198511000-00003	journal	January 1985
Huntington Disease G. Vonsattel, Jean Paul; DiFiglia, Marian Journal of Neuropathology and Experimental Neurology, Vol. 57, Issue 5 https://doi.org/10.1097/00005072-199805000-00001	journal	January 1998
Hemigramicidin-TEMPO conjugates: Novel mitochondria-targeted antioxidants Fink, Mitchell P.; Macias, Carlos A.; Xiao, Jingbo Critical Care Medicine, Vol. 35, Issue Suppl https://doi.org/10.1097/01.CCM.0000279192.96303.E7	journal	January 2007
Treatment With a Novel Hemigramicidin-TEMPO Conjugate Prolongs Survival in a Rat Model of Lethal Hemorrhagic Shock Macias, Carlos A.; Chiao, Jeffrey W.; Xiao, Jingbo Annals of Surgery, Vol. 245, Issue 2 https://doi.org/10.1097/01.sla.0000236626.57752.8e	journal	January 2007
Abnormalities in the Tricarboxylic Acid Cycle in Huntington Disease and in a Huntington Disease Mouse Model Naseri, Nima N.; Xu, Hui; Bonica, Joseph Journal of Neuropathology & Experimental Neurology, Vol. 74, Issue 6 https://doi.org/10.1097/NEN.0000000000000197	journal	June 2015
Therapeutic effects of coenzyme Q10 (CoQ10) and reduced CoQ10 in the MPTP model of Parkinsonism: Coenzyme Q10 and MPTP Cleren, Carine; Yang, Lichuan; Lorenzo, Beverly Journal of Neurochemistry, Vol. 104, Issue 6 https://doi.org/10.1111/j.1471-4159.2007.05097.x	journal	October 2007
Mutant Huntingtin Impairs Axonal Trafficking in Mammalian Neurons In Vivo and In Vitro Trushina, Eugenia; Dyer, Roy B.; Badger, John D. Molecular and Cellular Biology, Vol. 24, Issue 18 https://doi.org/10.1128/MCB.24.18.8195-8209.2004	journal	September 2004
Is There a Link between Mitochondrial Reserve Respiratory Capacity and Aging? Desler, Claus; Hansen, Thomas Lau; Frederiksen, Jane Bruun Journal of Aging Research, Vol. 2012 https://doi.org/10.1155/2012/192503	journal	January 2012
Creatine supplementation in Parkinson disease: A placebo-controlled randomized pilot trial Bender, A.; Koch, W.; Elstner, M. Neurology, Vol. 67, Issue 7 https://doi.org/10.1212/01.wnl.0000238518.34389.12	journal	October 2006
Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington’s Disease Budworth, Helen; Harris, Faye R.; Williams, Paul PLOS Genetics, Vol. 11, Issue 8 https://doi.org/10.1371/journal.pgen.1005267	journal	August 2015
Automated Tracking of Animal Posture and Movement during Exploration and Sensory Orientation Behaviors Gomez-Marin, Alex; Partoune, Nicolas; Stephens, Greg J. PLoS ONE, Vol. 7, Issue 8 https://doi.org/10.1371/journal.pone.0041642	journal	August 2012
Targeting Mitochondrial Dysfunction and Neurodegeneration by Means of Coenzyme Q10 and its Analogues Orsucci, D.; Mancuso, M.; Ienco, E. Caldarazzo Current Medicinal Chemistry, Vol. 18, Issue 26 https://doi.org/10.2174/092986711796957257	journal	September 2011
Co-Enzyme Q10 to Treat Neurological Disorders: Basic Mechanisms, Clinical Outcomes, and Future Research Direction Salama, Mohamed; Yuan, Ti-Fei; Machado, Sergio CNS & Neurological Disorders - Drug Targets, Vol. 12, Issue 5 https://doi.org/10.2174/18715273113129990071	journal	July 2013
Prolonged Intake of Coenzyme Q10 Impairs Cognitive Functions in Mice Sumien, Nathalie; Heinrich, Kevin R.; Shetty, Ritu A. The Journal of Nutrition, Vol. 139, Issue 10 https://doi.org/10.3945/jn.109.110437	journal	August 2009

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