Inhibition of Excessive Monoamine Oxidase A/B Activity Protects Against Stress-induced Neuronal Death in Huntington Disease.

Jolene Ooi,Michael R Hayden,Mahmoud A Pouladi

doi:10.1007/s12035-014-8974-4

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-014-8974-4) contains supplementary material, which is available to authorized users.

Highlights

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder that has no known cure
We show that Monoamine oxidases (MAO)-A/B promoter fragments of up to 2 kb were transcriptionally active in both STHdhQ7/Q7 and STHdhQ111/Q111 cells and, importantly, that the transcriptional activity at the MAO-A/B promoter loci was significantly increased in STHdhQ111/Q111 cells compared to STHdhQ7/Q7 cells (Fig. 1c)
To determine if increased MAO activity plays a role in the reduction of cell viability, we introduced MAO inhibitors upon the start of serum deprivation

Summary

Introduction

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder that has no known cure. It is caused by an expansion of a CAG trinucleotide repeat within exon 1 of the huntingtin (HTT) gene, where the onset of motor symptoms and severity of neuropathology are dependent on the size of the trinucleotide expansion [1, 2]. In R6/2 mice, significant deficits are observed in extracellular and tissue levels of striatal dopamine and in D1-class dopamine receptor signaling [5, 8,9,10]. Baseline and evoked extracellular levels of striatal dopamine are reduced in YAC128 HD mice [5, 10, 11]. In post mortem HD brains, there is a reduced number of striatal D1R- and D2R-

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