September 10, 2015 report
Closer look at proteins involved in Parkinson's disease reveals segment involved in amyloid formation
α-synuclein is a protein found most often in the tips of nerve cells and is believed to be involved in communication between neurons via lipid binding. In some cases, however, α-synuclein performs abnormally and causes fibrils to form—such fibrils tend to migrate causing damage to brain tissue and associated neurodegeneration—this is what happens in Parkinson's disease, which is still incurable. In this new study, the researchers took a closer look at a stretch of amino acids that are part of the makeup of α-synuclein—peptides corresponding to residues 68–78. Noting that crystals that form the core of them are too small to view with optical microscopy (because they are smaller than the wavelength of light) the team instead used micro-electron diffraction. Doing so allowed them to see not just the peptides, but pairs of face-to-face β-sheets, which are believed to be the building blocks of fibrils.
Most prior research has implicated residues located between 30 and 53 as the main culprit involved in the development of Parkinson's disease, but now, according to the results of this new research, it appears that residues between 68 and 78 may play a role as well. The researchers suggest that this region may interact with the more studied region in ways that cause enhanced fibril formation to occur.
Goedert and Cheng note that the newly uncovered structural information could help in the development of molecules able to inhibit the formation of α-synuclein fibrils, and thus serve as a means of stopping the progression of such degenerative diseases.
The protein α-synuclein is the main component of Lewy bodies, the neuron-associated aggregates seen in Parkinson disease and other neurodegenerative pathologies. An 11-residue segment, which we term NACore, appears to be responsible for amyloid formation and cytotoxicity of human α-synuclein. Here we describe crystals of NACore that have dimensions smaller than the wavelength of visible light and thus are invisible by optical microscopy. As the crystals are thousands of times too small for structure determination by synchrotron X-ray diffraction, we use micro-electron diffraction to determine the structure at atomic resolution. The 1.4 Å resolution structure demonstrates that this method can determine previously unknown protein structures and here yields, to our knowledge, the highest resolution achieved by any cryo-electron microscopy method to date. The structure exhibits protofibrils built of pairs of face-to-face β-sheets. X-ray fibre diffraction patterns show the similarity of NACore to toxic fibrils of full-length α-synuclein. The NACore structure, together with that of a second segment, inspires a model for most of the ordered portion of the toxic, full-length α-synuclein fibril, presenting opportunities for the design of inhibitors of α-synuclein fibrils.
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