Functional amyloid formation within mammalian tissue

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 question: are M{alpha} amyloid fibers serving a function in melanin synthesis? After reconstituting components of the melanin biosynthethic pathway in vitro, they showed that adding rM{alpha} results in a 2-fold increase in melanin production (as does adding other amyloids like A{beta} and {alpha}-synuclein). Perhaps more importantly, the M{alpha} amyloid fibrils bind and orient the highly reactive organic melanin precursors, mitigating the cellular toxicity observed when M{alpha} amyloid production is halted by mutation.

The authors also raise the intriguing idea that, given the propensity for many proteins to form amyloid fibrils, this conformation may be another physiologically important protein fold found in cells. To differentiate the biologically functional amyloid from pathogenic amyloids, the authors suggest using the term "amyloidin." Although the common involvement of amyloids between melanin synthesis and protein conformation disorders is most surprising, future research into the differences between amyloid formation in these processes may hold the key for understanding diseases including Huntington, Parkinson and Alzheimer disease. Because melanosome biogenesis is a tightly regulated process, a deeper understanding of the mechanisms that allow the Pmel17 M{alpha} fragment to avoid the toxic stage of amyloid formation could provide considerable insight into which aspects are missing when proteins misfold.


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