The unfolding of amyloid's true colors

What do neurodegenerative diseases and suntans have in common? Scientists at the Scripps Research Institute have found an intriguing molecular connection. In neurodegenerative disorders such as Alzheimer and Parkinson disease, proteins aggregate into specific fibrous structures (called a cross-{beta} sheet) to form insoluble plaques known as amyloid that are highly toxic to cells. But in a new study in PLoS Biology, Douglas Fowler, Atanas Koulov, and colleagues present evidence that the amyloid structure may also play a normal role in the formation of the sunburn-fighting pigment, melanin, in mammalian cells.

Melanin is synthesized in organelles called melanosomes, which reside in specialized skin cells (melanocytes) and the eyes (retinal pigment epithelium), to produce and traffic pigments for coloration, ultraviolet protection, and chemical detoxification. The researchers isolated melanosomes from retinal pigment epithelium and were surprised to find the organelle loaded with fibrillar amyloids of the glycoprotein Pme117, a critical player in the formation of melanosomes.

During the formation of melanosomes, Pme117 lyses into two fragments, one called M{alpha}. After confirming that the amyloids were comprised of M{alpha} fibers, the authors tried to make M{alpha} fragments fold into amyloid in a test tube. They showed that a purified, nonaggregated M{alpha} (which they called recombinant rM{alpha}) folds into amyloids remarkably quickly. In fact, rM{alpha} formed amyloids at a rate four orders of magnitude faster than the rate of formation for other well-known amyloids--A{beta} and {alpha}-synuclein, which are implicated in Alzheimer and Parkinson disease, respectively. The authors offer the intriguing hypothesis that by rapidly folding into the amyloid cross-{beta} sheet structure, M{alpha} avoids generating the toxic intermediates that are very common in pathogenic amyloid formation.

Finally, Fowler et al. satisfy a burning questio

Contact: Paul Ocampo
Public Library of Science

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