Inhibition of Excessive Monoamine Oxidase A/B Activity Protects Against Stress-induced Neuronal Death in Huntington Disease.
Monoamine oxidases (MAO) are important components of the homeostatic machinery that maintains the levels of monoamine neurotransmitters, including dopamine, in balance. Given the imbalance in dopamine levels observed in Huntington disease (HD), the aim of this study was to examine MAO activity in a mouse striatal cell model of HD and in human neural cells differentiated from control and HD patient-derived induced pluripotent stem cell (hiPSC) lines. We show that mouse striatal neural cells expressing mutant huntingtin (HTT) exhibit increased MAO expression and activity. We demonstrate using luciferase promoter assays that the increased MAO expression reflects enhanced epigenetic activation in striatal neural cells expressing mutant HTT. Using cellular stress paradigms, we further demonstrate that the increase in MAO activity in mutant striatal neural cells is accompanied by enhanced susceptibility to oxidative stress and impaired viability. Treatment of mutant striatal neural cells with MAO inhibitors ameliorated oxidative stress and improved cellular viability. Finally, we demonstrate that human HD neural cells exhibit increased MAO-A and MAO-B expression and activity. Altogether, this study demonstrates abnormal MAO expression and activity and suggests a potential use for MAO inhibitors in HD.
Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore, 138648, Singapore.
Jolene
J
Ooi
Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore, 138648, Singapore.|Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
Michael R
MR
Hayden
Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore, 138648, Singapore. pouladi@tlgm.a-star.edu.sg.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore. pouladi@tlgm.a-star.edu.sg.
Mahmoud A
MA
Pouladi
D000818:Animals; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism*; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D008995:Monoamine Oxidase; D004298:Dopamine
Human-induced pluripotent stem cells; Huntington’s disease; Monoamine oxidase; Monoamine oxidase inhibitors; Oxidative stress; Striatal neural cells