Abstract
The relatively high co-occurrence of Parkinson’s disease (PD) and melanoma has been established by a large number of epidemiological studies. However, a clear biological explanation for this finding is still lacking. Ultra-violet radiation (UVR)-induced skin melanin synthesis is a defense mechanism against UVR-induced damage relevant to the initiation of melanoma, whereas, increased neuromelanin (NM), the melanin synthesized in dopaminergic neurons, may enhance the susceptibility to oxidative stress-induced neuronal injury relevant to PD. SNCA is a PD-causing gene coding for alpha-Synuclein (α-Syn) that expresses not only in brain, but also in skin as well as in tumors, such as melanoma. The findings that α-Syn can interact with tyrosinase (TYR) and inhibit tyrosine hydroxylase (TH), both of which are enzymes involved in the biosynthesis of melanin and dopamine (DA), led us to propose that α-Syn may participate in the regulation of melanin synthesis. In this study, by applying ultraviolet B (UVB) light, a physiologically relevant stimulus of melanogenesis, we detected melanin synthesis in A375 and SK-MEL-28 melanoma cells and in SH-SY5Y and PC12 dopaminergic neuronal cells and determined effects of α-Syn on melanin synthesis. Our results showed that UVB light exposure increased melanin synthesis in all 4 cell lines. However, we found that α-Syn expression reduced UVB light-induced increase of melanin synthesis and that melanin content was lower when melanoma cells were expressed with α-Syn, indicating that α-Syn may have inhibitory effects on melanin synthesis in melanoma cells. Different from melanoma cells, the melanin content was higher in α-Syn-over-expressed dopaminergic neuronal SH-SY5Y and PC12 cells, cellular models of PD, than that in non-α-Syn-expressed control cells. We concluded that α-Syn could be one of the points responsible for the positive association between PD and melanoma via its differential roles in melanin synthesis in melanoma cells and in dopaminergic neuronal cells.
Highlights
Melanoma is the most dangerous form of skin cancers, characterized by uncontrolled growth of skin melanocytes, whereas, Parkinson’s disease (PD) is one of the neurodegenerative disorders, characterized by a progressive loss of pigmented dopamine (DA) neurons in the substantia nigra (SN)
We found that ultraviolet B (UVB) light irradiation increased melanin synthesis by 184%, 155% and by 179% in nona-Syn-overexpressed A375 melanoma cells, SH-SY5Y and PC12 neuronal cells respectively, whereas, it was increased by 160%, 148% and by 167% in wt-a-Syn-over-expressed A375 melanoma cells, SH-SY5Y and PC12 neuronal cells as compared to its nonUVB light-exposed control cells (Fig. 2A, 2C, 2D, lower panel)
Our results showed that UVB light exposure was associated with an increase of TYR activity by 160%, 138% and by 117% in non-a-Syn over-expressed A375, SH-SY5Y and PC12 cells, whereas, it was increased by 127%, 111% and 109% in a-Syn over-expressed A375, SH-SY5Y and PC12 cells as compared to its non-UVB light-exposed control cells (Fig. 3A, 3C, 3D)
Summary
Melanoma is the most dangerous form of skin cancers, characterized by uncontrolled growth of skin melanocytes, whereas, Parkinson’s disease (PD) is one of the neurodegenerative disorders, characterized by a progressive loss of pigmented dopamine (DA) neurons in the substantia nigra (SN). PD and melanoma are two different diseases, numerous epidemiological studies have established an increased incidence of melanoma in patients with PD and vice verse [1,2,3,4,5]. Skin melanin synthesis is considered as a defense mechanism against UVRinduced initiation of melanoma [14,15]. Melanin is a determinant of skin color Light skin color such as that in Caucasian populations contains less melanin. The findings that the incidence of both melanoma [14,16,17] and PD [18,19,20] is higher in Caucasian populations than that in black populations indicate that in addition to melanoma, low skin melanin level may enhance the vulnerability to PD
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