Autophagy enhancement is rendered ineffective in presence of α-synuclein in melanoma cells

Abstract

Increased cellular concentration of α-synuclein (α-syn) predisposes it to misfolding and aggregation that in turn impair the degradation pathways. This poses a limitation to the use of overexpression models for studies on α-syn clearance by autophagy, which is widely investigated for its therapeutic potential. This limitation can be overcome with the use of endogenous models. In this study, SK-MEL-28, a melanoma cell model with endogenous α-syn expression, was employed to study α-syn clearance through autophagy. We demonstrated the dual localization of α-syn to nucleus and cytoplasm that varied in response to changes in cellular environment. Autophagy inhibition and exposure to dopamine favored cytoplasmic localization of α-syn, while autophagy induction favored increased localization to the nucleus. The inhibitory effect of dopamine on autophagy was heightened in presence of α-syn. Additionally, because α-syn had a regulatory effect on autophagy, cells showed an increased resistance to autophagy induction in presence of α-syn. This resistance prevented effective induction of autophagy even under conditions of prolonged autophagy inhibition. These results highlight alternate physiological roles of α-syn, particularly in non-neuronal cells. Because autophagy enhancement could reverse neither the increase in α-syn levels nor the autophagy inhibition, there arises a need to evaluate the efficacy of autophagy-based therapeutic strategies.

Linking Parkinson's Disease and Melanoma: Interplay Between α‐Synuclein and Pmel17 Amyloid Formation

“…Along these lines, we reported endogenous detection of α‐syn within nuclei of SK‐MEL 28 cells (Fig. 1B), an observation supported by other studies also showing nuclear localization of α‐syn in melanocytes/melanoma 68,69,74,110,115 . Although not in the context of melanoma, α‐syn has been shown to localize to nuclei of neuronal‐like cells and modulate gene expression by interacting with nucleosomes, 116 histones, 117‐120 and regulatory regions of genes 121,122 .…”

“…1B), an observation supported by other studies also showing nuclear localization of α-syn in melanocytes/melanoma. 68,69,74,110,115 Although not in the context of FIG. 2.…”

“…Given that both melanocytes and dopaminergic neurons are derived from the neural crest, 123 this leads us to ask if α‐syn could behave similarly in melanocytes and melanoma. In addition, future studies should also focus on understanding how autophagy is impacted by α‐syn, because it has been suggested to promote cell survival in melanoma 69,115 yet promote cell death in PD 124 …”

“…Given that both melanocytes and dopaminergic neurons are derived from the neural crest, 123 this leads us to ask if α-syn could behave similarly in melanocytes and melanoma. In addition, future studies should also focus on understanding how autophagy is impacted by α-syn, because it has been suggested to promote cell survival in melanoma 69,115 yet promote cell death in PD. 124 To conclude, we have described the unique epidemiological and molecular connections between PD and melanoma, detailing how α-syn could act to disrupt melanogenesis in melanoma cells by a multipronged approach of disrupting enzymes involved in melanin biosynthesis (TH and TYR), as well as modulating Pmel17 functional amyloid formation (Fig.…”

Are Glucosylceramide-Related Sphingolipids Involved in the Increased Risk for Cancer in Gaucher Disease Patients? Review and Hypotheses

“…Indeed, its expression is higher in the skin of patients with melanoma compared to that of healthy subjects. α-Synuclein could contribute to cancer development by inhibiting autophagy [97]. Its aggregation would result from GCase loss-of-function and, consequently, GlcCer and/or GlcSph accumulation, as shown in PD neuronal cells [98] and in GD/PD mouse models [99].…”