Abstract
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.
Highlights
Similar to the peripheral melanin biosynthetic pathway, the multifunctional enzyme tyrosinase (EC 1.14.18.1; monophenol monooxygenase) in the brain catalyzes the conversion of Ltyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA) and oxidizes L-DOPA to form dopa quinone, which is a melanin precursor
Increased expression of tyrosinase-positive signals on the injected side of the striatum was lasted at 14 days after injection of liposome-entrapped tyrosinase in both sham-operated and hemi-parkinsonian animals compared with the injected side in lipofectin-injected mice or the non-injected side in each tyrosinase-injected mice (Figure S1B)
The main findings of this study are: (1) transplantation of tyrosinase-producing cells into the striatum resulted in marked amelioration of the apomorphine-induced abnormal rotation behavior with increase in L-DOPA and DA in hemi-parkinsonian animal models, and (2) intrastriatal transplantation of melanocytes from the back skin as clinically available tyrosinase-expressing cells showed lasting improvement in the apomorphine-induced rotation behavior in hemi-Parkinson’s disease (PD) model mice, with increase in DA-positive signals around the surviving transplants
Summary
Similar to the peripheral melanin biosynthetic pathway, the multifunctional enzyme tyrosinase (EC 1.14.18.1; monophenol monooxygenase) in the brain catalyzes the conversion of Ltyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA) and oxidizes L-DOPA to form dopa quinone, which is a melanin precursor. It is known that tyrosinase oxidizes dopamine (DA) to rapidly form melanin via the DA quinone [1]. A previous study has demonstrated that DA quinone, the formation of which is enhanced by tyrosinase, inactivates tyrosine hydroxylase (TH) [5]. Supplement of DA synthesis by tyrosinase has been reported in TH null mice [6]. These findings imply that tyrosinase may be involved in catecholaminergic cell function, and that the activity of this enzyme may contribute to the pathogenesis or complementary reaction associated with Parkinson’s disease (PD)
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