Defining an amyloid link Between Parkinson's disease and melanoma
| Autor: | Dexter N. Dean, Jennifer C. Lee |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Amyloid animal diseases alpha-synuclein Fibril Biochemistry Melanin 03 medical and health sciences chemistry.chemical_compound Protein Aggregates 0302 clinical medicine Protein Domains Cell Line Tumor Organelle medicine Humans Melanoma Melanosome Alpha-synuclein Multidisciplinary Melanosomes fibril aggregation Parkinson Disease functional amyloid Biological Sciences medicine.disease In vitro Cell biology nervous system diseases Biophysics and Computational Biology 030104 developmental biology chemistry nervous system Physical Sciences 030217 neurology & neurosurgery gp100 Melanoma Antigen |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | An epidemiological connection exists between Parkinson’s disease (PD) and melanoma. α-Synuclein (α-syn), the hallmark pathological amyloid observed in PD, is also elevated in melanoma, where its expression is inversely correlated with melanin content. We present a hypothesis that there is an amyloid link between α-syn and Pmel17 (premelanosomal protein), a functional amyloid that promotes melanogenesis. Using SK-MEL 28 human melanoma cells, we show that endogenous α-syn is present in melanosomes, the organelle where melanin polymerization occurs. Using in vitro cross-seeding experiments, we show that α-syn fibrils stimulate the aggregation of a Pmel17 fragment constituting the repeat domain (RPT), an amyloidogenic domain essential for fibril formation in melanosomes. The cross-seeded fibrils exhibited α-syn−like ultrastructural features that could be faithfully propagated over multiple generations. This cross-seeding was unidirectional, as RPT fibrils did not influence α-syn aggregation. These results support our hypothesis that α-syn, a pathogenic amyloid, modulates Pmel17 aggregation in the melanosome, defining a molecular link between PD and melanoma. |
| Databáze: | OpenAIRE |
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