Treatment with diphenyl–pyrazole compound anle138b/c reveals that α-synuclein protects melanoma cells from autophagic cell death

Elisa Turriani,Andrei Leonov,Sergey Ryazanov,Margarete Schön,Armin Giese,Diana F Lázaro,Michael P Schön,Christian Griesinger,Tiago F Outeiro,Dorothea Becker,Donna J Arndt-Jovin

doi:10.1073/pnas.1700200114

Abstract

Recent epidemiological and clinical studies have reported a significantly increased risk for melanoma in people with Parkinson's disease. Because no evidence could be obtained that genetic factors are the reason for the association between these two diseases, we hypothesized that of the three major Parkinson's disease-related proteins-α-synuclein, LRRK2, and Parkin-α-synuclein might be a major link. Our data, presented here, demonstrate that α-synuclein promotes the survival of primary and metastatic melanoma cells, which is the exact opposite of the effect that α-synuclein has on dopaminergic neurons, where its accumulation causes neuronal dysfunction and death. Because this detrimental effect of α-synuclein on neurons can be rescued by the small molecule anle138b, we explored its effect on melanoma cells. We found that treatment with anle138b leads to massive melanoma cell death due to a major dysregulation of autophagy, suggesting that α-synuclein is highly beneficial to advanced melanoma because it ensures that autophagy is maintained at a homeostatic level that promotes and ensures the cell's survival.

Highlights

Recent epidemiological and clinical studies have reported a significantly increased risk for melanoma in people with Parkinson’s disease
To determine which of these three genes/proteins that are strongly linked to Parkinson’s disease (PD) are expressed in the different stages of melanoma development and to what extent, we probed the same tissues of a nevus > melanoma progression tissue microarray (TMA) [15] with antibody to the respective protein encoded by the genes SNCA, PARK8, or PARK2
Because our analysis demonstrated the strongest expression of α-synuclein in TMA cores representing advanced melanoma, we queried the Gene Expression Omnibus (GEO) Dataset GSE4587 from a wholegenome expression profiling study that we had previously conducted [16] for the level of expression of the SNCA gene in tissues ranging from normal skin > metastatic growth phase (MGP) melanoma

Summary

Introduction

Recent epidemiological and clinical studies have reported a significantly increased risk for melanoma in people with Parkinson’s disease. Our data, presented here, demonstrate that α-synuclein promotes the survival of primary and metastatic melanoma cells, which is the exact opposite of the effect that α-synuclein has on dopaminergic neurons, where its accumulation causes neuronal dysfunction and death. Because this detrimental effect of α-synuclein on neurons can be rescued by the small molecule anle138b, we explored its effect on melanoma cells. Using the Utah Cancer Registry as a resource, it was reported [8] that PD patients and their relatives have a significantly elevated risk for melanoma and, that relatives of patients with melanoma have an increased risk for PD Given this finding, the authors postulated that there is a genetic association between PD and melanoma. A family-based matched cohort study, conducted in Swe-

Methods

Results

Conclusion