Defining an amyloid link Between Parkinson's disease and melanoma.
| Autor: | Dean DN; Laboratory of Protein Conformation and Dynamics, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892., Lee JC; Laboratory of Protein Conformation and Dynamics, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892 leej4@nhlbi.nih.gov. |
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| Jazyk: | angličtina |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Sep 15; Vol. 117 (37), pp. 22671-22673. Date of Electronic Publication: 2020 Aug 31. |
| DOI: | 10.1073/pnas.2009702117 |
| Abstrakt: | 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. Competing Interests: The authors declare no competing interest. (Copyright © 2020 the Author(s). Published by PNAS.) |
| Databáze: | MEDLINE |
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