The fibrous protein aggregates known as amyloid are defined by their characteristic ß-sheet structure, but they are perhaps best known to clinicians for their prominent appearance in several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and familial polyneuropathies. Amyloid’s status as a solely pathogenic entity in humans may be in danger, however.

Researchers at the Scripps Research Institute in La Jolla, California, recently discovered the first known functional human amyloid, which appears to protect melanocytes from harm during melanin formation. And that may be only the beginning. Despite amyloid’s less-than-stellar reputation, "the usage of amyloid in biology may be as common as other canonical protein folds," the authors speculated.

"We’ve begun to compare and contrast this physiologic, functional amyloid with pathologic amyloid, in terms of both their formation and what they might do," said study coauthor Jeffery W. Kelly, PhD, Dean and Professor of Chemistry at Scripps, in an interview with Neurology Reviews. "We’re hoping that this will provide some unique insights into the pathologic mechanism and how to intervene in [amyloid-related] neurodegenerative diseases."

In recent years, researchers studying prokaryotes and invertebrates have found that amyloid is a key component in a variety of biological structures, ranging from spider silk to the robust fibers that link together Escherichia coli cells in biofilms. For mammals, however, the conventional wisdom has been that the phrase "functional amyloid" is most likely an oxymoron: The toxicity associated with intracellular or extracellular amyloid presumably precluded any useful role within mammal cells. It’s probably not the amyloid fibrils themselves that are toxic and pathogenic, Dr. Kelly noted, but rather the process of forming the structure. Emerging evidence implicates the oligomeric amyloidogenic intermediates as toxic entities. Perhaps the most striking example is familial amyloid polyneuropathy, according to Dr. Kelly. "When you do biopsies [in the early stages of the disease], you don’t find amyloid, but you find a lot of amyloidogenic proteins deposited," he said. "But if you look at those patients years later, you begin to see the amyloid fibrils, and then at some point these fibrils become the dominant species. However, the amyloid itself isn’t necessarily what is responsible" for pathogenesis.

FUNCTIONAL FIBERS

In the new report, which appeared in PLoS Biology, Dr. Kelly and colleagues investigated the Mα subunit of Pmel17, a key melanosomal protein. Findings from electron microscopy, x-ray diffraction, and other biostructural techniques revealed that the diameter, diffraction patterns, and spectral characteristics of Mα aggregates are all consistent with an amyloid structure. Moreover, the investigators found that MΑ assembles into amyloid fibers at a rate several orders of magnitude faster than do amyloid ß and α-synuclein, suggesting that this particular amyloid is a normal, functional, evolutionarily preserved structure.

The fact that Mα more than doubled the rate of melanin formation also points to this being a functional amyloid, although skeptics might argue that this rate enhancement is miniscule compared to that seen with enzymes, Dr. Kelly noted. "But we think that the rate enhancement is only part of the reason that the amyloid fibrils are there," he said. "I would argue that the biologically important reason is that the amyloid fibrils bind to these very reactive melanin precursors and keep them in the melanosome and template them for polymerization."

The benefit of keeping melanin’s precursors sequestered is apparent from studies of mice that cannot make Pmel amyloid fibers; the animals’ melanocytes are much less viable, "presumably owing to the toxicity of the melanin precursors that are produced," Dr. Kelly said. He added that it is tempting to speculate that these findings may be particularly relevant to Parkinson’s disease, in which the affected brain region (the substantia nigra) contains a good deal of melanin, but he cautioned that the melanin in the substantia nigra has a somewhat different structure than its dermatologic counterpart.

PATHOGENIC PROCESSES

It is not clear exactly why amyloid’s intermediates are so cytotoxic. "Some people think they poke holes in cellular membranes," Dr. Kelly noted, while others think "that the amyloid fibrils and their precursors bind to—and titrate away—essential cellular proteins." Dr. Kelly himself favors a less dramatic but broader pathogenic process. "I don’t think there’s a single aberrant pathway that causes the neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s, but rather a lot of pathways that are interfered with by the process of amyloid formation. Multiple little things go wrong in the cell, which ultimately causes the demise of the neuron." Although amyloid diseases affect many organ systems, neurons may be particularly vulnerable because of their large size, their role in the secretion of large amounts of neurotransmitters and protein, and their limited ability to regenerate.

Dr. Kelly predicted that amyloids will turn out to serve a variety of important functions in mammalian cells, most likely in roles where they can be confined to organelles. He noted that proteins designed de novo in the laboratory frequently end up forming not the predicted structure but amyloid fibrils. "It’s sort of the default structure for proteins. So I would be shocked if nature didn’t find a use for amyloid in virtually all organisms."

NR

—Peter Doskoch

Suggested Reading
Fowler DM, Koulov AV, Alory-Jost C, et al. Functional amyloid formation within mammalian tissue. PLoS Biol. 2005;4:e6.

Return to table of contents