Transplantation of Melanocytes Obtained from the Skin Ameliorates Apomorphine-Induced Abnormal Behavior in Rodent Hemi-Parkinsonian Models

Tyrosinase, which catalyzes both the hydroxylation of tyrosine and consequent oxidation of L-DOPA to form melanin in melanocytes, is also expressed in the brain, and oxidizes L-DOPA and dopamine. Replacement of dopamine synthesis by tyrosinase was reported in tyrosine hydroxylase null mice. To examine the potential benefits of autograft cell transplantation for patients with Parkinson’s disease, tyrosinase-producing cells including melanocytes, were transplanted into the striatum of hemi-parkinsonian model rats or mice lesioned with 6-hydroxydopamine. Marked improvement in apomorphine-induced rotation was noted at day 40 after intrastriatal melanoma cell transplantation. Transplantation of tyrosinase cDNA-transfected hepatoma cells, which constitutively produce L-DOPA, resulted in marked amelioration of the asymmetric apomorphine-induced rotation in hemi-parkinsonian mice and the effect was present up to 2 months. Moreover, parkinsonian mice transplanted with melanocytes from the back skin of black newborn mice, but not from albino mice, showed marked improvement in the apomorphine-induced rotation behavior up to 3 months after the transplantation. Dopamine-positive signals were seen around the surviving transplants in these experiments. Taken together with previous studies showing dopamine synthesis and metabolism by tyrosinase, these results highlight therapeutic potential of intrastriatal autograft cell transplantation of melanocytes in patients with Parkinson’s disease.

酪氨酸酶（Tyrosinase）可同时催化酪氨酸的羟化反应，并将左旋多巴（L-DOPA）进一步氧化，从而在黑素细胞（melanocytes）中合成黑色素；该酶亦在大脑中表达，可氧化左旋多巴与多巴胺。有研究报道，在酪氨酸羟化酶（tyrosine hydroxylase）基因敲除小鼠体内，可通过酪氨酸酶实现多巴胺合成的替代途径。为探究自体细胞移植治疗帕金森病（Parkinson’s disease）患者的潜在获益，研究人员将包括黑素细胞在内的产酪氨酸酶细胞，移植至经6-羟基多巴胺（6-hydroxydopamine）损毁的半帕金森模型大鼠或小鼠的纹状体（striatum）内。纹状体内黑色素瘤细胞移植术后第40天，即可观察到阿扑吗啡诱导的旋转行为得到显著改善。移植稳定合成左旋多巴的转酪氨酸酶cDNA肝癌细胞后，半帕金森模型小鼠的不对称阿扑吗啡诱导旋转行为得到显著改善，该疗效可持续长达2个月。此外，将新生黑色小鼠背部皮肤来源的黑素细胞移植至帕金森模型小鼠体内（而非白化小鼠来源的黑素细胞），可使小鼠的阿扑吗啡诱导旋转行为改善效果持续至移植后3个月。此类实验中，在存活的移植物周围可观测到多巴胺阳性信号。结合此前关于酪氨酸酶可催化多巴胺合成与代谢的研究，上述结果凸显了纹状体内黑素细胞自体移植在帕金森病患者治疗中的潜在应用价值。