Parkinson’s Disease and Melanoma: Co-Occurrence and Mechanisms

Co-existence of PD and melanoma

A large number of epidemiological studies have reported a co-occurrence of PD in melanoma patients and melanoma in PD patients, and the incidence is significantly higher than expected [16–21]. The largest prospective study of melanoma in PD so far involved a total of 2,106 patients with a mean age of 68.6 years, 85 of whom were receiving levodopa. It was found that in these patients age- or sex-adjusted relative risk of any melanoma was more than seven times than expected [21]. Another large scale study demonstrated that the diagnosis of melanoma is associated with a 50% increased risk of the development of PD [18] and patients with PD had a two-fold increase in risk of developing melanoma subsequently [19]. In another study that included ∼160,000 people who did not have PD, it was found that individuals who had a family history of melanoma were twice as likely to develop PD in comparison to individuals who did not have history of melanoma in the family [20]. A recent clinical study has shown that in Phase I, patients with PD had a 3.8-fold increased chance of having melanoma that pre-existed as compared with controls and in Phase II, patients with melanoma had a 4.2-fold increased risk for the development of PD. Interestingly, patients who had melanoma without PD had a 10.5-fold increased relative risk of dying from metastatic melanoma compared with patients who had melanoma along with PD [22]. It has also been recently reported that the risk for the development of melanoma was higher than expected in the NET-PD LS-1 cohort with an overall standardized event ratio of 3.6 (95% CI, 2.2–5.6) and this result was similar to the risk reported in earlier comparable clinical trial cohorts [8].

Common markers between PD and melanoma

Transcranial sonograms of the midbrain of PD patients commonly show an extended echogenic substantia nigra (SN), a pigmented region of the midbrain, consistent with degeneration of dopaminergic nigrostriatal projection neurons. An abnormally extended echogenic SN was also observed in melanoma patients, supporting a potential underlying pathogenic pathway common to both diseases [23]. Furthermore, melanoma patients exhibiting abnormally echogenic SN demonstrated increased prodromal motor and non-motor features typical of PD, such asymmetric motor slowing, although hyposmia and colour vision disturbance were not frequently observed [24]. Higher echogenicity of SN in melanoma correlated with lower serum iron, as also observed for PD. Parkinsonism was most commonly observed in patients with the lentigo-maligna type of melanoma, typically located at head or neck areas exposed to sun.

Role of melanin in melanoma

The higher incidence of melanoma in light skinned people than in dark skinned populations suggests that melanin may play a protective role in melanoma [28, 29]. This is also supported by the observations that high melanin density is associated with reduced development of melanomas and other cancers that are sun-induced [28] whereas low melanin density such as in the upper arms is linked to increased incidence of melanoma [30]. This protective effect of melanin may be explained by the ability of melanin to absorb or scatter the UVR, dissipating the UVR energy and preventing DNA damage, which leads to malignant melanoma and other skin cancers. It has been reported that levodopa, an intermediate in the biosynthesis of the pigment melanin, selectively inhibits the growth of human melanoma cells but not of non-pigmented control cells [31], suggesting that induction of melanin synthesis correlates with inhibition of cell proliferation [31, 32] and also suggesting another mechanism by which high melanin levels may lead to a reduction in the susceptibility of cells to develop into melanoma Fig. 2.

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Fig. 2

Schematic representation of possible mechanisms that can explain the co-occurrence of PD and melanoma.

Role of neuromelanin in PD

In the SN, neuromelanin is responsible for the dark pigmentation of the dopaminergic neurons. In the brains of PD patients, loss of these dopaminergic neurons causes decreased levels of neuromelanin in the SN, but there has been no correlation reported in the levels of neuromelanin in the SN of PD patients of different race. It has been suggested that neuromelanin formation may be neuroprotective because it can scavenge toxic dopaquinone and help in sequestering metal ions such as copper, iron, cadmium and manganese [33, 34] in human nigral neurons. Lack of neuromelanin makes the neurons more susceptible to oxidative stress [35, 36] and leads to impairment of motor function [35]. The lower occurrence of PD in the black population than in Caucasian populations suggests that, in analogy to the higher cutaneous melanin synthesis, there may be a higher neuromelanin synthesis in the black population, enhancing the protective effects in the SN against external toxic substances [35, 36].

It has also been suggested that melanosis (excessive production of melanin) might protect against both PD and melanoma. This is supported by studies that show a negative association between tobacco smoking and PD [37, 38]. In smokers, melanosis occurs as a result of increased melanin synthesis [39, 40] because nicotine can stimulate activity of melanocytes and production of melanin or the capability of melanin to bind to noxious substances generated by tobacco smoke [39, 40]. Increased melanosis in smoking PD patients therefore may explain the protective effect of smoking against PD.

Levodopa and melanoma

A number of studies have reported that levodopa may increase the risk of developing melanoma [62, 63] but this still remains controversial. Levodopa is a substrate for tyrosine hydroxylase, a key enzyme in the production of melanin, and melanoma tumor cells are rich in this enzyme. This raises the possibility that levodopa may facilitate tumor growth. There have been several reports demonstrating that melanoma developed in PD patients at a higher-rate rate than expected even before onset of symptoms of PD or the start of dopaminergic therapy. One report of a patient who had PD and developed melanoma after the starting of L-dopa therapy [62] suggested that L-dopa “should not be used in patients with a history of malignant melanoma or undiagnosed skin lesion because it may cause activation of malignant melanoma”. However, systematic analysis of reports came to the conclusion that the co- occurrence of both PD and melanoma is a coincidence rather than causal [64] and that it is unlikely that there is an association between L-dopa and induction or progression of malignant melanoma [65]. The role of levodopa therapy has been debated in the DATATOP clinical trial cohort. Observed cases of malignant melanoma (N = 5) were compared to the published expected values (N = 1.5) for a standard healthy population. The standardized event ratio was 3.3 (95% confidence interval, 1.1–7.8), indicating that incidence of malignant melanoma was higher than expected in this PD cohort. However, there was no association between levodopa treatment and the incidence of melanoma [65]. Collectively, these studies strongly suggest that there is little link between levodopa-therapy and melanoma [63–67].

Common genetic associations link PD and melanoma

Environmental toxins and genes interact and are presumably involved in PD. Lower detoxification enzyme activity may play a crucial role in pathogenesis of PD [68, 69]. The genes CYP2D6 and GSTM1 encode enzymes that have been reported to play important roles in responses of cells to endogenous and/or exogenous reactive intermediates, thereby influencing the susceptibility of an individual to developing PD [70, 71]. The presence of null polymorphism in the GSTM1 gene can result in the lack of expression of the enzyme, and can cause neuronal death that may contribute to PD [71, 72]. CYP2D6 is believed to be involved in PD because of its role in the regulation of drug and toxin metabolism, but studies linking the relation of PD to CYP2D6 are inconsistent [71, 72]. It has also been reported that polymorphisms in VDR are involved in PD pathogenesis [73]. High frequency of polymorphisms of CYP2D6 or the polymorphism of VDR and null for GSTM1 gene, are found in melanoma patients as well, suggesting that variations in CYP2D6 and VDR or GSTM1 genes may increase the risk for both melanoma and PD. In addition it has been shown that mutations in PLA2G6 are also associated with both PD and melanoma [74, 75], suggesting a further mechanistic link between PD and melanoma (Fig. 1A).

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Fig. 1

Genes responsible for melanoma and PD. A) CYP2D6 or GSTM1, VDR, MC1R gene alterations are found in both PD and Melanoma, providing a potential link between PD and Melanoma. B) Mutations in parkin, α-synuclein, LRRK2, DJ-1, and other PARK genes may underlie the co-occurrence of PD and Melanoma. TRPM7 and p53 are additional genes altered in PD and melanoma.

Melanoma is strongly associated with a phenotype of fair skin/red hair caused by loss-of-function polymorphisms in the MC1R (melanocortin 1 receptor) gene. One study reported that MC1R is not associated with the co-occurrence of melanoma and PD [76] but another study reported that MC1R variant p.R160W (rs1805008) is marginally associated with PD and modulated the risk of PD in the Spanish population [77]. A recent study has reported that MC1R may be protective in the dopaminergic system, suggesting MC1R as a potential therapeutic target for PD. Since the role of MC1R has already been established in melanoma, MC1R may be involved in a common pathogenic pathway for PD and melanoma [78]. Another possible mechanism linking cutaneous (lentigo-maligna) melanoma and PD may be polymorphisms in the MC3/MC4 melanocortin receptor (MC3R, MC4R) genes which might alter signaling by their ligand, β-melanocyte-stimulating hormone [79, 80].

Links between mutations of PD-related genes and co-occurrence with melanoma

Exposure to pesticides

There is a well-known link between pesticides that target the mitochondrial electron transfer pathway and PD, including rotenone and paraquat [97]. It has been shown that paraquat and rotenone increase endogenous α-synuclein in SH-SY5Y cells as well as in SK-MEL-2 cell lines and also increase α-synuclein levels in virally transduced SH-SY5Y and SK-MEL2 cells overexpressing WT or A53T mutant α-synuclein, suggesting that exposure to pesticides can play a role in development of PD and melanoma simultaneously [98] (Fig. 2).

The role of rare variants in PD and melanoma

Rare variants analysis across all genes, per gene, or for any individual variant does not show any significant trends among different carrier frequencies between controls and PD, in different models of inheritance, in the following cutaneous malignant melanoma (CMM) risk genes: DCC, BAP1, KIT, ERBB4, MAPK2, PTEN, TP53 and MITF. TYR p.V275F which is a rare variant, and is a pathogenic allele for recessive albinism, was found to be more common in PD cases than in controls, suggesting that this might be a new gene in the dopamine-biosynthetic pathway that could play a role in susceptibility to PD and, since pigmentation genes contribute to CMM, possibly contribute to a link between PD and melanoma [99].

Transient receptor potential melastatin 7 gene

Transient receptor potential melastatin 7 (TRPM7) is a cation channel that is nonspecific and has an enzyme domain [100]. It is expressed in melanoma cell lines, and is involved in melanocyte survival by detoxification of intermediates formed as a result of melanogenesis [101, 102]. A heterozygous variant of TRPM7 has been reported in some PD patients with dementia and some Guamanian patients [103] (Fig. 1B).

Tumor suppressor gene p53

The tumor suppressor gene p53 has been shown to play a role in human neurodegenerative disorders like PD. Therefore, chemical inhibitors of p53 may be effective in suppressing the neurodegenerative process in PD [104]. Loss of p53 function occurs in many human tumors including melanoma [105]. Therefore, it is possible that there may be reduced risk for PD in melanoma patients who harbor the inactivating p53 mutations. Factors like p53 that promote one disorder while protecting against the other may explain the fact that comorbidity between PD and melanoma is imperfect (Fig. 1B).

Role of tyrosine hydroxylase in PD and melanoma

The enzyme tyrosine hydroxylase (TH) is involved in the conversion of tyrosine to DOPA, the rate-limiting step in the biosynthesis of DA within dopaminergic neurons [106, 107]. In PD, there is a loss of TH in the striatum. The most effective treatment of PD is with the use of DOPA, DA agonists, or inhibitors of DA catabolism. However, an excess of cytosolic DA can form reactive intermediates, such as dopaquinone and reactive oxygen species that are associated with dopaminergic neuronal cell loss. Thus TH, an essential enzyme critical for synthesis of DA, also facilitates the formation of ROS that can cause oxidative stress leading to neuronal loss in PD [106]. TH is also found in human melanoma cells [108]. In skin melanocytes, TH is involved in catalyzing the conversion of tyrosine to DOPA, thereby generating the substrate and activator for tyrosinase, the enzyme that catalyzes the first and rate-limiting step in the biosynthetic pathway of melanin [108] Fig 2.

Role of tyrosinase in PD and melanoma

Tyrosinase (TYR) is a copper-dependent rate-limiting enzyme in melanin synthesis within the melanosomes in the skin [109]. It has been shown that the activity of TYR is low in white skin and high in black skin, and it also controls melanogenesis [109, 110]. In the biosynthetic pathway of melanin, tyrosinase is involved in catalyzing several reactions, including the hydroxylation of tyrosine to DOPA [111]. Tyrosinase is also involved in the oxidation of DOPA to dopaquinone, which then leads to the formation of melanin, eumelanin and pheomelanin [110, 112]. A number of reactive intermediates, such as dopaquinone, which are generated during the process of pigmentation, and formation of melanosomes which are catalyzed by TYR, are involved in the induction of melanocytotoxicity [110, 112]. Although melanocytotoxicity may lead to the inhibition of growth in melanoma cells, the exact role of TYR in the process of malignant change is not well understood since the activity of TYR varies among different melanoma tissues [113]. In most pigmented melanomas, positive TYR activity has been reported, whereas negative TYR activity occurs in both pigmented and non-pigmented melanomas [113]. Thus the enzymatic activity of TYR does not appear to reflect the behavior of the tumor cells, suggesting that TYR activity may not robustly predict the degree or malignancy of melanoma. It has been shown that TYR is also involved in the synthesis of neuromelanin in SN of mice and humans [113, 114]. In the mouse brain, the TYR promoter is active throughout the brain during development, particularly in the SN of adult brain [115]. A recent study has also shown that secretion of neuronal TYR is also involved in the inhibition of apoptosis [116] Therefore the overexpression of TYR in brain can play either a neuroprotective role because of the formation of neuromelanin [33] or play a toxic role due to the formation of melanin precursors, such as DOPA and dopaquinone [117] Fig. 2.

α -synuclein: Role in pigmentation

α-synuclein is highly expressed in melanoma cells, but those cells that express high levels of α-synuclein generate very low levels of or no melanin pigment [114], which can be explained by α-synuclein’s role in the reduction of tyrosine hydroxylase activity [107, 118]. Therefore it can be hypothesized that in the melanocytes from the skin of patients suffering from PD, increased α-synuclein causes inhibition of TH, which leads to decrease in melanin synthesis [109] leading in turn to the increasing the risk for melanoma.

DA neurons in SN and melanocytes in skin both express tyrosinase. When excess α-synuclein accumulates under pathological conditions in DA neurons, tyrosinase may interact directly with α-synuclein, causing local modifications that hinder the physiological functions of α-synuclein [119] and leading to toxic processes, such as increases in DA and dopaquinone levels in the cytosol, which then lead to injury of mitochondria [120] and eventual death of neurons [121]. Furthermore, increased levels of α-synuclein can interact with dopaquinone or other DA metabolites to form intermediates that are toxic, leading directly to neuronal cell death [121, 122].