Nanotools for Megaproblems:  Probing Protein Misfolding Diseases Using NanomedicineModusOperandi

Abstract

Misfolding and self-assembly of proteins in nanoaggregates of different sizes and morphologies (nanoensembles, primary nanofilaments, nanorings, filaments, protofibrils, fibrils, etc.) is a common theme unifying a number of human pathologies termed protein misfolding diseases. Recent studies highlight increasing recognition of the public health importance of protein misfolding diseases, including various neurodegenerative disorders and amyloidoses. It is understood now that the first essential elements in the vast majority of neurodegenerative processes are misfolded and aggregated proteins. Altogether, the accumulation of abnormal protein nanoensembles exerts toxicity by disrupting intracellular transport, overwhelming protein degradation pathways, and/or disturbing vital cell functions. In addition, the formation of inclusion bodies is known to represent a major problem in the production of recombinant therapeutic proteins. Formulation of these therapeutic proteins into delivery systems and their in vivo delivery are often complicated by protein association. Thus, protein folding abnormalities and subsequent events underlie a multitude of human pathologies and difficulties with protein therapeutic applications. The field of medicine therefore can be greatly advanced by establishing a fundamental understanding of key factors leading to misfolding and self-assembly responsible for various protein folding pathologies. This article overviews protein misfolding diseases and outlines some novel and advanced nanotechnologies, including nanoimaging techniques, nanotoolboxes and nanocontainers, complemented by appropriate ensemble techniques, all focused on the ultimate goal to establish etiology and to diagnose, prevent, and cure these devastating disorders.

α-Synuclein Misfolding: Single Molecule AFM Force Spectroscopy Study

“…7,8 However, a number of critical questions, such as why the misfolded conformation of the protein is formed, why this conformation is critical for the protein assembly into the aggregates, and how the aggregation process starts and proceeds remain unanswered. Importantly, we need to detect and analyze the conformation of misfolded protein before aggregation.…”

Early Stages for Parkinson’s Development: α-Synuclein Misfolding and Aggregation

“…High-resolution methods such as x-ray crystallography, nuclear magnetic resonance (NMR), electron microscopy, and atomic force microscopy (AFM) have provided some information regarding the secondary structure of aggregated proteins and morphologies of self-assembled aggregates (reviewed in Lyubchenko et al 2006;Uversky et al 2006), but several questions such as why the misfolded conformation of the protein is formed, and how the misfolded protein aggregates, remain unanswered. Importantly, we need to identify the conformation of misfolded protein prior to aggregation.…”

Hyperspectral imaging (HSI) to evaluate the interaction of optically active nanoparticles in biological media and cells

“…A number of diseases are also associated with the accumulation of fibrillar intracellular deposits or are associated with the buildup of nonfibrillar deposits." 28 Protein molecules normally exist in the properly folded, soluble form. As a disorder of protein metabolism, protein misfolding can result from the intracellular disruption of chaperoning and the disruption of the protein degradation pathway.…”