Home
This Title All WIREs
WIREs RSS Feed
How to cite this WIREs title:
WIREs Nanomed Nanobiotechnol
Impact Factor: 6.14

Nanoimaging for protein misfolding diseases

Full article on Wiley Online Library:   HTML PDF

Can't access this content? Tell your librarian.

Abstract 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. WIREs Nanomed Nanobiotechnol 2010 2 526–543 This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

Dynamic force spectroscopy (DFS) analysis of CGNNQQNY interactions measured at pH 5.6. (a) DFS plot and (b) schematic profile of energy landscape for dissociation of CGNNQQNY dimer at pH 5.6, where the first barrier is located at ∼0.2 Å with 24.5 kBT of energy barrier and the second barrier is at ∼5.7 Å with 28.9 kBT.

[ Normal View | Magnified View ]

(a) The dynamic force spectroscopy plot for the atomic force microscopy probing of α‐synuclein interaction measured at pH 3.7. (b) The corresponding energy landscape profile for the α‐synuclein dimer dissociation at pH 3.7. The heights of energy for the inner and outer barriers are 26.4 and 29.8 kBT, respectively. The lifetimes for the two states of the dimer (outer and inner barriers) are 1.35 s and 50 ms, respectively.

[ Normal View | Magnified View ]

(a) The dynamic force spectroscopy plot for the atomic force microscopy probing of α‐synuclein interaction measured at pH 5.1 The lifetime for the dimer dissociation is 0.27 s. (b) The profile of the energy landscape for the α‐synuclein dimer dissociation at pH 5.1. It shows a one‐barrier energy path. The energy barrier height is 28.1 kBT.

[ Normal View | Magnified View ]

Probing of the interaction between α‐synuclein molecules. Scheme (a) shows a representative force curve between α‐synuclein molecules at pH 5.1. The rupture event is indicated with an arrow. Plate (b) shows the rupture force distribution histogram obtained for multiple experiments performed at pH 5.1 at apparent loading rate 3953 pN/s. The solid line is the fit of the experimental data with the probability density function distribution, which provides the maximal rupture force 44.6 ± 1.2 pN.

[ Normal View | Magnified View ]

Atomic force microscopy (AFM) experimental setup to probe the interaction between α‐synuclein monomers. Scheme (a) schematically shows the α‐synuclein structure within micelles and (b) illustrates the immobilization of the surfaces. α‐Synuclein was attached to the MAS functionalized AFM tip (top) by covalent bonds with Cys moiety of the protein. The mica surface (bottom) was functionalized with polyethylene glycol (PEG) treated with amynopropylsilatrane (APS‐mica, see Refs 64,65) surface.

[ Normal View | Magnified View ]

Schematic energy landscape profile. Dotted line is the original energy profile (E‐profile) in the absence of an external force. On the profile, G indicates the ground state, T the transition state, and D the dissociation state separated by potential barriers located at x0 and x1. External forces change the barrier heights. At small forces (F1x), the barrier at x1 remains taller than the barrier at x0. At large external force (F2x), the second potential barrier (x1) becomes lower than the first potential barrier (x0).

[ Normal View | Magnified View ]

Scheme for the atomic force microscopy (AFM) probing of misfolded interprotein interaction. The protein is tethered on the tip and on the substrate. (a) AFM tip and substrate before approaching; (b) AFM tip approaches the substrate which is capable of forming complex structure; (c) and (d) are two different complexes with low interaction forces (c) and strong interprotein interaction (d); (e) and (f) show two different force curves corresponding to scheme (c) and (d), respectively, where a and b are presented in the process of scheme (a) and (b). The peak at zero values of the tip‐sample separation is originated from the nonspecific interaction between tip and substrate.

[ Normal View | Magnified View ]

Wild type of Aβ‐40 and Aβ‐42 self‐assemble to form dimers and tetramers, but in further oligomerization, they have different pathways. Aβ‐40 fibrillizes slowly, but directly forms a compact square shape of tetramer. On the contrary, the open type of Aβ‐42 tetramers forms hexamers and dodecamers which are suggested as the primary stable intermediates for early stages of Aβ‐42 aggregation. (Adapted with permission from Ref 35. Copyright 2009 Nature Publishing Group: Nature Chemistry).

[ Normal View | Magnified View ]

Normalized kinetic curves of aggregation of short peptide from Sup35 yeast prion protein at various pH values: pH 7.0 (green triangles, tlag = 49 h), pH 5.6 (blue diamonds, tlag = 11 h), pH 3.7 (red dots, tlag = 19 h), and pH 2.0 (black squares, tlag = 195 h).

[ Normal View | Magnified View ]

A schematic representation of the protein dynamics. The transitions of the folded (native) state of the protein to unfolded and misfolded states are shown for the simplicity only. Characteristic times for the transition between these states as well as the dimer lifetime are shown above the arrows.

[ Normal View | Magnified View ]

The dynamic force spectroscopy (DFS) plot and energy landscape profile probing of Aβ‐40 interaction. Plates (a) and (b) show the DFS plot measured at pH 2.7 and 5.0, respectively. The corresponding energy profiles are shown in (c) (pH 2.7) and (d) (pH 5.0). The energy profiles show two barriers at x0∼0.6 Å with 24.8 kBT and x1∼4.3 Å with 30.3 kBT at pH 2.7 and at x0∼0.3 Å with 24.7 kBT and x1∼2.7 Å with 29.5 kBT at pH 5.0. The lifetime at each transition state was ∼10 ms and ∼2.7 s at pH 2.7 and ∼9 ms and ∼1.1 s at pH 5.0, respectively.

[ Normal View | Magnified View ]

Browse by Topic

Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

The latest WIREs articles in your inbox

Sign Up for Article Alerts