Many neurodegenerative diseases share a common pathological trait: misfolded proteins that aggregate into fibrils called amyloids. So joined, peptides take on new characteristics, such as exceptional strength and stiffness. Detailing these physical properties could help scientists better grasp the role of fibrils in disease. Writing in the November 3 Nature Photonics, scientists led by Bengt Nordén, Chalmers University of Technology, Gothenburg, Sweden, report that stacked together in fibrils, peptide monomers absorb more photons than they would on their own. This property could provide a way to track fibrillization in vitro and perhaps one day in vivo, the researchers suggest. Others were more cautious. David Teplow, University of California, Los Angeles, said that any clinical applications are a long way off, but the findings may prove useful. “The better we understand amyloid fibrils, the more clues we gain about how to develop therapeutic agents,” he told Alzforum.
First author Piotr Hanczyc was examining light absorption in various molecules when he stumbled upon an anomaly in insulin fibrils. Stuck together, insulin monomers absorbed extra photons. To explore this, Hanczyc turned his laser on other fibril types. He bombarded solutions of either monomeric or fibrillar lysozyme or α-synuclein with short bursts of visible and infrared light, and measured how much got absorbed. When heaped into fibrils, the subunits absorbed from two to five times the usual number of photons, depending on the wavelength of the light and the particular structure of the amyloid. The authors speculated that aromatic tyrosines that cram close together in the fibrils help dissipate energy and allow the peptides to absorb additional light. In support of that idea, more tyrosines and increasingly crowded subunits led to enhanced photon absorption.
Hanczyc proposed that this technique could help researchers deduce causes of fibrillization in vitro. By swapping amino acids within a given protein and seeing how they respond to light, researchers might tease out which changes foster or prevent the formation of fibrils. In theory, diagnostic or even treatment applications could follow, because infrared light does not damage tissue, said Hanczyc. For example, perhaps scientists could one day detect fibrils in the body using an imaging technique called laser-induced photoacoustic tomography, which measures ultrasound waves emitted by some cellular structures when they absorb light (see Wang et al., 2003). However, Hanczyc added that further research is needed to determine if other cellular components would distort the light signal from fibrils or if small oligomers would give off similar light signals. “We expect that the effect is related to the length of the fibrils,” he told Alzforum. “If they are too short, the enhancement [of photon absorption] might not be strong enough to detect.”
That could be a problem if the goal is to detect disease-related species, said Brigita Urbanc, Drexel University, Philadelphia. Low-molecular-weight oligomers are believed to be the toxic species in many neurodegenerative diseases, including Alzheimer’s. However, a detection method based on multiphoton-absorption could still be useful, Urbanc said, as it would complement new methods based on the intrinsic fluorescence of amyloid fibrils (see Chan et al., 2013). Unlike multiphoton absorption tests, intrinsic fluorescence does not depend on the presence of aromatic amino acids.
To expand on these findings, researchers should look at additional types of amyloid fibrils, said Teplow. That would allow them to more clearly determine how the structure of proteins, and the number and location of tyrosines, affects photon absorption.—Gwyneth Dickey Zakaib
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