Abstract
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.
Highlights
Postmortem brains from patients with Parkinson’s disease (PD) display regionally selective loss of nigrostriatal dopaminergic neurons, preferentially in the ventral tier of substantia nigra pars compacta (SNpc)[1,2,3]
We thereby examined the regulatory role of retinoic acid (RA) in MOR1 signaling in the nigrostriatal dopaminergic (nDA) neuron–depleted Pitx3ak/ak mice and found RA treatment upregulated MOR1 levels, mitigated L-DOPA–induced dyskinetic movements, and reduced a hyperactivation of protein kinase A (PKA)/ERK signaling seen in the dorsal striatum of Pitx3ak/ak mice, similar to Aldh1a1 knockouts
The ventral striatum is intensively innervated by ALDH1A1–positive fibers from DA neurons located in the ventral tegmental area (VTA); only a modest reduction of MOR1 expression was observed in ventral striatum of Aldh1a1−/− mice (Fig. 1B, Additional File 1: Fig. S2)
Summary
Postmortem brains from patients with Parkinson’s disease (PD) display regionally selective loss of nigrostriatal dopaminergic (nDA) neurons, preferentially in the ventral tier of substantia nigra pars compacta (SNpc)[1,2,3]. To investigate the relationship between ALDH1A1 and postsynaptic MOR1 expression, we examined MOR1 levels in Aldh1a1−/− mice. We thereby examined the regulatory role of RA in MOR1 signaling in the nDA neuron–depleted Pitx3ak/ak mice and found RA treatment upregulated MOR1 levels, mitigated L-DOPA–induced dyskinetic movements, and reduced a hyperactivation of PKA/ERK signaling seen in the dorsal striatum of Pitx3ak/ak mice, similar to Aldh1a1 knockouts. Together, these results reveal a previously unknown function of ALDH1A1 in upregulating postsynaptic μ-opioid receptor levels in the dorsal striosomes through transsynaptic RA signaling, thereby mitigating L-DOPA–induced dyskinetic movements
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