Department of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China.
Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Sci Rep. 2019 Mar 5;9(1):3602. doi: 10.1038/s41598-019-40326-x.
Aldehyde dehydrogenase 1A1 (ALDH1A1), a retinoic acid (RA) synthase, is selectively expressed by the nigrostriatal dopaminergic (nDA) neurons that preferentially degenerate in Parkinson's disease (PD). ALDH1A1-positive axons mainly project to the dorsal striatum. However, whether ALDH1A1 and its products regulate the activity of postsynaptic striatal neurons is unclear. Here we show that μ-type opioid receptor (MOR1) levels were severely decreased in the dorsal striatum of postnatal and adult Aldh1a1 knockout mice, whereas dietary supplement of RA restores its expression. Furthermore, RA treatment also upregulates striatal MOR1 levels and signaling and alleviates L-DOPA-induced dyskinetic movements in pituitary homeobox 3 (Pitx3)-deficient mice that lack of ALDH1A1-expressing nDA neurons. Therefore, our findings demonstrate that ALDH1A1-synthesized RA is required for postsynaptic MOR1 expression in the postnatal and adult dorsal striatum, supporting potential therapeutic benefits of RA supplementation in moderating L-DOPA-induced dyskinesia.
醛脱氢酶 1A1（ALDH1A1）是一种维甲酸（RA）合成酶，选择性表达于黑质纹状体多巴胺能（nDA）神经元，后者在帕金森病（PD）中优先退化。ALDH1A1 阳性轴突主要投射到背侧纹状体。然而，ALDH1A1 及其产物是否调节纹状体内突触后神经元的活性尚不清楚。本文作者表明，在新生和成年 Aldh1a1 敲除小鼠的背侧纹状体中，μ 型阿片受体（MOR1）水平严重降低，而 RA 的膳食补充则恢复了其表达。此外，RA 处理还上调纹状体 MOR1 水平和信号转导，并缓解了缺乏表达 ALDH1A1 的 nDA 神经元的垂体同源盒 3（Pitx3）缺陷型小鼠的 L-DOPA 诱导的运动障碍。因此，这些发现表明，ALDH1A1 合成的 RA 是新生和成年背侧纹状体中突触后 MOR1 表达所必需的，支持 RA 补充在调节 L-DOPA 诱导的运动障碍方面具有潜在的治疗益处。
