Sirt1/FoxO1-Associated MAO-A Upregulation Promotes Depressive-Like Behavior in Transgenic Mice Expressing Human A53T α-Synuclein
Yong Li, Qian Jiao, Xixun Du, Hong Jiang
Abstract
Nonmotor symptoms are of pivotal importance in Parkinson’s disease (PD), among which depressive disorder occurs in more than 45% of PD cases. Decreased levels of noradrenaline (NA) and serotonin (5-HT) in the central nervous system are relevant to it; however, the underlying mechanism is largely unknown. To this end, we conducted behavioral assays to analyze the depressive phenotype in transgenic mice with overexpressed A53T human α-synuclein (A53T mice) and examined alterations of NAergic and 5-HTergic systems in the neuron degeneration, neurotransmitter production, and degradation aspects of the mouse. As compared to controls, A53T mice displayed elevated depressive-like behavior at 6 months, which presents earlier than motor deficits do at 12 months. We detected reduced levels of NA and 5-HT in the hippocampus and NA in the locus coeruleus of 6-month A53T mice. There was no loss of NAergic and 5-HTergic neurons or decreased neurotransmitter synthesis in the brain. However, the expression of MAO-A, an enzyme responsible for NA and 5-HT degradation, was upregulated in A53T mice. Mechanistically, Sirt1 was downregulated which lead to an increase in FoxO1 acetylation, which subsequently increased the transcription of MAO-A. Activation of Sirt1 by resveratrol or inhibition of MAO-A by moclobemide administration could restore brain NA and 5-HT levels and attenuate the depressive-like behavior of A53T mice. Taken together, our results provided a novel correlation between Sirt1 and MAO-A, and compounds targeting on these molecules are beneficial for improving depression in the A53T mouse model of PD.