. Functional amyloid formation within mammalian tissue. PLoS Biol. 2006 Jan;4(1):e6. PubMed.

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  1. This paper and comment draw attention to other types of physiological amyloids or fibrillar structures that subserve normal funcitons. Examples include the elastins (e.g., Tamburro et al., 2005), as well as the complex network of filaments (from actin microfilaments to intermediate filaments) that also provide a scaffold and other functions needed by nearly all cell types. The existence of these normal filamentous poylmers that promote cell function and viablitiy will help dissect out how and why abnormal amyloid filaments exert deleterioius, pathological effects. It will also help us address the question of when, and by what mechanisms, they might serve a protective function in disease states.

    View all comments by John Trojanowski
  2. Functional amyloid and nonfunctional interpretations

    Fowler et al. report results of studies of the biophysical behavior of
    the
    bovine melanosome protein Pmel17 and of the potential role of this protein in melanin biosynthesis. The data strongly support the conclusion that Pmel17, under appropriate conditions, rapidly assembles into amyloid-type polymers and that these polymers support melanin synthesis. The demonstration of a
    physiologically beneficial role of Pmel17 amyloid adds another example
    to a growing list of prokaryotic and eukaryotic proteins for which
    amyloid formation serves an important role in normal cellular
    function. In some respects, however, the authors' view of the
    relative importance of these findings to larger questions of
    prokaryotic and eukaryotic cell biology and the role of amyloid is
    unsupported experimentally and thus must be considered
     "nonfunctional."

    One of the most interesting observations of Fowler et al. was the rate
    of amyloid formation by Pmel17 (a half-time of roughly 1 second). This
    rate was four orders of magnitude larger than the rates observed for
    the Alzheimer and Parkinson disease-linked proteins amyloid
    β-protein and α-synuclein, respectively. This is a very
    interesting and important result, because investigation of its
    mechanistic basis has the potential to reveal structural factors
    controlling amyloid formation not only by Pmel17 but also by many
    others of the approximately 20 known amyloid proteins. The authors
    suggest that this rate may be a result of evolutionary pressures to
    minimize production of toxic intermediates in amyloid formation. This
    may be so, but this teleological interpretation remains unsupported
     experimentally.

    This commentator is largely ignorant about melanosome biology, but one may postulate that factors other than "toxic intermediates" may have contributed with equal (or greater) importance to the protein evolution of Pmel17. For example, rapid assembly kinetics makes processes linked to Pmel17 assembly remarkably sensitive, and thus controllable, in temporal and
    concentration "regimes." Also, because Pmel17 assembly occurs within a
    specialized organelle—the early melanosome—any intermediates would
    be sequestered from other cellular compartments that might be
    sensitive to their toxic effects.

    The high rate of Pmel17 assembly raises questions about how this
    specific process can be integrated into the prevailing view that
    amyloid proteins share a common core structural organization. How does
    one reconcile a rate constant that is four orders of magnitude larger
    than those of other amyloid proteins with a "common structure"? Do the
    noncore regions of Pmel17 contribute to the population of the
    amyloid-competent conformational state by the nascent, proteolytically
    processed Pmel17 protein?

    Studies of melanin biosynthesis in vitro suggest that Pmel17 amyloid
    formation is linked to increased synthesis rates. The authors suggest
    that this "is the first example of an amyloid that functions in a
    chemical reaction." This may be so, but the argument would be
    strengthened if greater mechanistic insight existed. The suggestion
    that spatial organization of the substrate used in the experiments
    (DHQ) might be involved is quite reasonable and lends itself to future
    hypothesis testing.

    I question the proposition that a "general name amyloidin" be
    designated for "functional amyloid." Historically, terms have been
    created to define new entities and this process has helped scientists
    by standardizing meaning, facilitating communication and clarity of
    thought. The authors have done a superb job of characterizing the
    Pmel17 assembly product as amyloid, the classical fibrillar structure
    defined by its dye-binding characteristics, secondary structure, x-ray
    diffraction pattern, and morphology. Structurally, how does an
    amyloidin differ from an amyloid? How do you distinguish amyloids
    (which by definition have similar core structures) that have
    beneficial or detrimental effects that are context (intracellular,
    extracellular, or organ-specific milieu)-specific? This naming
    exercise becomes a semantic endeavor with little benefit, creating
    more obfuscation than clarification. How does one name a new amyloid
    protein that in the future may be found to have a beneficial effect?
    One would think initially that the protein is "nonfunctional" and
    name it amyloid, when in fact it is an amyloidin under some
    conditions. I suggest we maintain our current terminology and simply
    define under what conditions specific amyloid proteins have beneficial
    or detrimental physiologic effects.