First Observation of Excitation Motion of Single Protein Molecules during Aggregation Process— Leading to New Treatment Strategies for Alzheimer’s Disease (Press Release)
- Release Date
- 01 Nov, 2017
- BL40XU (High Flux)
November 2, 2017
Key research findings
・First ever observation of repeated formation and dissolution of protein molecular assemblies (networks) associated with vigorous Brownian motion*1.
・Establishment of high-speed measurement technology to observe the dynamics of single protein molecules during aggregation with high accuracy and detection of localized excitation motion common to inorganic, organic, and protein systems.
・Enabling the observation of single molecules during the molecular aggregation process that may be strongly associated with the onset process of Alzheimer’s disease, leading the way to brand-new treatment strategies to control or suppress molecular aggregation.
Amyloidosis*2, which is known as the abnormal aggregation of biological protein molecules, is said to be related to more than 20 diseases including nervous system disorders such as Alzheimer’s disease and Parkinson’s disease, endocrine diseases such as type II diabetes, and prion disease. However, effective treatments have not yet been established for these diseases. A major reason that effective solutions have not yet been developed is the lack of information about the dynamic behavior of protein molecules in biological solutions. To establish technologies for observing and measuring the local dynamics of single molecules in protein solutions, a research group has been focusing on molecular aggregation in supersaturated solutions*3 as a model case of aggregation processes. The joint research group consists of Professor Yuji Sasaki at the Graduate School of Frontier Sciences, the University of Tokyo [concurrently affiliated with AIST-UTokyo Advanced Operando-Measurement Technology Open Innovation Laboratory (OPERANDO-OIL), National Institute of Advanced Industrial Science and Technology (AIST)], and researchers from Osaka University, Kobe University, and JASRI. The group has observed the vigorous motion in and around protein molecules (lysozyme) during the aggregation process in supersaturated solutions by applying the diffracted X-ray tracking (DXT)*4 technique. Detailed analysis of the results showed that the vigorous motion generates extremely small force fields*6 of femtonewton*5 magnitude. The results indicated that the formation and dissolution of protein assemblies (networks) associated with vigorous Brownian motion occur repeatedly. The research achievements enabled the observation of single molecules during molecular aggregation, which is strongly associated with the onset process of Alzheimer’s disease, which is expected to lead to the development of brand-new treatment strategies based on the supersaturation phenomenon. Article |
＜Glossary＞
*1 Brownian motion
The random motion (rotation and translation) of nanoparticles (gold nanocrystals in this research) in solutions. Detailed information about solutions, including viscosity, density, and flow velocity, can be obtained by analyzing Brownian motion.
*2 Amyloidosis
Amyloidosis is defined as a group of diseases characterized by the deposition of amyloids, which are water-insoluble protein molecules, in organs, causing functional disorders. When observed with an electron microscope, amyloids are fibrillar structures 8 to 15 nm in diameter. It is known that various biological protein molecules can form amyloids.
*3 Supersaturated solutions
The state of a solution wherein it contains more dissolved material than it could normally contain but still remains stable without precipitation. This phenomenon is observed in a wide range of solutions including those of inorganic, organic, and protein molecules. The supersaturation phenomenon is not only at the core of crystallization technology but is also applied for a wide range of purposes in medical and industrial areas including heat storage technologies using latent heat (the heat released during crystallization), drug development aimed at the efficient transport of poorly soluble drugs throughout the body, and morphological control (shape, size, and monodispersity) in the preparation of nanomaterials.
*4 Diffracted X-ray tracking (DXT)
In the DXT technique, protein molecules or aggregates whose dynamic properties are to be evaluated are labeled with gold nanocrystals with size on the order of 10 nm, and the nanocrystal motion is monitored from the trajectory of Laue diffraction spots from the gold nanocrystals using high-speed time-resolved X-ray diffraction images. Professor Yuji Sasaki devised the technique in 1998 and published his achievement in 2000. Since then, he has measured the internal motion of single protein molecules and published the results in journals such as Physical Review Letters, Physical Review, BBRC, Cell, Biophysical Journal, and Scientific Reports. The figure above is a diagram of the DXT technique. At present, DXT is the only way to detect dynamic molecular aggregates (inhomogeneous structures).
*5 Femtonewton
Femto- (symbol f) is a unit prefix in the International System of Units (SI) denoting a factor of 10-15 (0.000000000000001 or a quadrillionth). Newton (symbol N) is the SI unit of force. A newton is the force that causes an object of mass 1 kg to accelerate by 1 m/s2. For example, the force required to suppress the Brownian motion of nanoparticles is thought to be femtonewton order (one ten-quadrillionth of the gravity acting on a weight of 1 kg), which is greater than the gravity or viscous force acting on nanoparticles. This is also expressed as a femtogram or as the gravity acting on a water droplet of 0.1 µm diameter.
*6 Force fields
The regions of space where the force acting on an object is unambiguously defined on the basis of the position of the object. The Brownian motion of single protein molecules was measured in this research. Usually, there are no force fields in the case of free Brownian motion and the relationship between time and completely free random motion is measured. In this experiment, the motion increased with time. The force fields are considered to be associated with the formation of protein molecular aggregates.
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