Nanoimaging for protein misfolding diseases.
Misfolding and aggregation of proteins are widespread phenomena leading to the development of numerous neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases. Each of these diseases is linked to structural misfolding and aggregation of a particular protein. The aggregated forms of the protein induce the development of a particular disease at all levels, leading to neuronal dysfunction and loss. Because protein refolding is frequently accompanied by transient association of partially folded intermediates, the propensity to aggregate is considered a general characteristic of the majority of proteins. X-ray crystallography, nuclear magnetic resonance, electron microscopy, and atomic force microscopy have provided important information on the structure of aggregates. However, fundamental questions, such as why the misfolded conformation of the protein is formed, and why this state is important for self-assembly, remain unanswered. Although it is well known that the same protein under pathological conditions can lead to the formation of aggregates with diverse biological consequences, the conditions leading to misfolding and the formation of the disease prone complexes are unclear, complicating any development of efficient prevention of the diseases. Misfolded states exist transiently, so answering these questions requires the use of novel approaches and methods. Progress has been made during the past few years, when recently developed ensemble methods and single-molecule biophysics techniques were applied to the problem of the protein misfolding. In this review, the impacts of these studies on the understanding of the mechanisms of the protein self-assembly into aggregates and on the development of treatments of the diseases are discussed.
Lyubchenko
Yuri L
YL
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198-6025, USA. ylyubchenko@unmc.edu
Kim
Bo-Hyun
BH
Krasnoslobodtsev
Alexey V
AV
Yu
Junping
J
D018360:Crystallography, X-Ray; D003952:Diagnostic Imaging / Q000379:methods*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D018625:Microscopy, Atomic Force; D008854:Microscopy, Electron; D050997:Nanomedicine / Q000379:methods*; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D057165:Proteostasis Deficiencies / Q000175:diagnosis* / Q000378:metabolism
D011506:Proteins