Parkinson’s disease (PD) is a progressive movement disorder affecting about 1.8% of people over the age of 65, characterized by the degeneration of the midbrain dopaminergic neurons in the substantia nigra. It is predominantly a sporadic disease, but about 10% of cases can be attributed to Mendelian inheritance. Neurodegenerative diseases are often associated with decreased cancer risk.However PD patients have an increased risk of melanoma and it has been proposed that the two conditions may share some biological pathways. Dopaminergic neurons in the substantia nigra produce a form of melanin known as neuromelanin (NM), a dark polymer pigment that shares common features with the melanin formed in melanocytes in order to protect the skin from Ultraviolet radiation. As yet, it is unknown if NM differs in PD patients, but physiological roles which may influence neuronal viability have been proposed to include scavenging of free radicals and chelation of transition metals such as Fe. Melanocytes have a neural crest origin and melanoma cells are known to express high levels of α-synuclein, a protein associated with PD. The melanosome is a specialised melanocyte-specific storage organelle for melanin that shares some features with late endosomal compartments.
LRRK2 is a multi-domain protein, which uniquely possesses both protein kinase and GTPase catalytic activities. Autosomal dominant mutations of LRRK2 represent one of the principal genetic risk factors for Parkinson’s Disease (PD), which results in preferential loss of neuromelanin containing neurons from the substantia nigra. The (patho)physiological roles of LRRK2 are currently unclear. However, it has been linked to the regulation of endolysosmal membrane trafficking through complex formation with other Parkinson’s related genes (Rab7L and Vps35). LRRK2 is a large protein (2527 amino acids), mutations in which, are prominently associated with both familial and sporadic PD. Small molecule inhibitors of LRRK2 kinase activity have been developed and are commercially available. By interrogating the Broad Institute’s Cancer Cell line Encyclopedia, we noticed that LRRK2 and another PD-associated protein (α-synuclein) are particularly highly expressed in melanoma cells and furthermore that six genes associated with melanosome biogenesis/pigmentation such as tyrosinase (TYR) and melanin A are in the top 20 genes expressed across >1000 cell lines that are most correlated with LRRK2 expression.
The overall objective is to introduce melanocyte model systems to the host laboratory and to establish LRRK2 substrates or cellular consequences of activity which may be specific to melanin-containing cells.
