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.

中文翻译：

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Sirt1 / FoxO1相关的MAO-A上调促进表达人类A53Tα-突触核蛋白的转基因小鼠的抑郁样行为。

非运动性症状在帕金森氏病（PD）中至关重要，其中抑郁症发生在超过45％的PD病例中。中枢神经系统中去甲肾上腺素（NA）和5-羟色胺（5-HT）水平降低与其相关；但是，基本机制尚不清楚。为此，我们进行了行为分析，以分析过度表达A53T人α-突触核蛋白的转基因小鼠中的抑郁表型（A53T小鼠），并研究了NAergic和5-HTergic系统在神经元变性，神经递质产生和降解方面的变化。老鼠。与对照组相比，A53T小鼠在6个月时表现出较高的抑郁样行为，这比12个月时的运动障碍表现得更早。我们检测到6个月的A53T小鼠海马中NA和5-HT水平降低，以及蓝斑中NA降低。在大脑中没有NAergic和5-HTergic神经元的丢失或神经递质合成的减少。但是，MAO-A（一种负责NA和5-HT降解的酶）的表达在A53T小鼠中被上调。机械上，Sirt1被下调，这导致FoxO1乙酰化增加，随后增加了FoxO1的转录。毛-A。白藜芦醇对Sirt1的激活或吗氯贝胺对MAO-A的抑制可恢复脑NA和5-HT水平，并减轻A53T小鼠的抑郁样行为。两者合计，我们的结果提供了Sirt1和MAO-A之间的新型关联，并且针对这些分子的化合物有利于改善PD的A53T小鼠模型中的抑郁症。