Nanoscale Imaging of Protein Aggregates in Huntington’s Disease
Protein aggregation is a hallmark of neurodegenerative diseases such as Huntington’s, Alzheimer’s and Parkinson’s disease. The proteins responsible for neurodegeneration misfold and form clumps, or aggregates. In the case of Huntington’s disease, Htt aggregates later change shape to form branches and give rise to other fibrils by more clumping or breakage of the initial fibrils. Although disease severity has been related to the size of these aggregates, it is unclear if aggregates play a causative role or a protective role in disease formation. It is thought that morphological changes of aggregates might explain the disease mechanism; if so, studying aggregate formation will aid development of potential therapies for diseases such as Huntington’s. Using super-resolution (SR) fluorescence imaging, scientists at Stanford University distinguished single molecules of Huntingtin (Htt) protein with nanometer precision within protein aggregates.
SR imaging has emerged as a powerful new tool to visualize fine biomolecular architecture at the nanoscale level. Unlike the long fibrils seen in other neurodegenerative diseases, Huntington’s Htt aggregates form short, intricate branches, challenging the limits of optical imaging techniques, due to their fine structure. The investigators attached Htt aggregates to a photoactivatable fluorescent dye that emits light in a fluctuating manner, giving a “blinking” appearance. This allowed localization of single molecules that were twelve nanometers apart within the aggregates. In this work, Moerner and colleagues have successfully applied the power of this high resolution imaging technique to a germane biological problem, thereby providing the first single molecule snapshots of the aggregates associated with Huntigton’s disease. Earlier single molecule studies had been unable to hone in at the nanometer dimension. With this innovative application of SR imaging to observe Htt aggregates, scientists can next move on to image protein aggregates in real-time to understand Htt and other neurodegenerative proteins in their cellular environments.
The work was supported by the NIH Nanomedicine Development Center for Protein Folding Machinery, which is developing nanoscale approaches to correct misfolded proteins in neurodegenerative diseases.
Publication citation and link:
Duim WC, Chen B, Frydman J, Moerner WE (2011). Sub-Diffraction Imaging of Huntingtin Protein Aggregates by Fluorescence Blink-Microscopy and Atomic Force Microscopy.
Chemphyschem.12:1-4.
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