The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity.

Amyloid beta 42 (Abeta42) is the principal trigger of neurodegeneration during Alzheimer's disease (AD). However, the etiology of its noxious cellular effects remains elusive. In a combinatory genetic and proteomic approach using a yeast model to study aspects of intracellular Abeta42 toxicity, we here identify the HSP40 family member Ydj1, the yeast orthologue of human DnaJA1, as a crucial factor in Abeta42-mediated cell death. We demonstrate that Ydj1/DnaJA1 physically interacts with Abeta42 (in yeast and mouse), stabilizes Abeta42 oligomers, and mediates their translocation to mitochondria. Consequently, deletion of YDJ1 strongly reduces co-purification of Abeta42 with mitochondria and prevents Abeta42-induced mitochondria-dependent cell death. Consistently, purified DnaJ chaperone delays Abeta42 fibrillization in vitro, and heterologous expression of human DnaJA1 induces formation of Abeta42 oligomers and their deleterious translocation to mitochondria in vivo. Finally, downregulation of the Ydj1 fly homologue, Droj2, improves stress resistance, mitochondrial morphology, and memory performance in a Drosophila melanogaster AD model. These data reveal an unexpected and detrimental role for specific HSP40s in promoting hallmarks of Abeta42 toxicity.

Oleophobic textiles with embedded liquid and vapor hazard detection using differential planar microwave resonators.

Protective clothing must repel hazardous liquids such as oils, acids, and solvents, which often exhibit low surface tension. The low surface tension liquid repellency of textiles is currently characterized qualitatively, considering only the first thirty seconds of wetting. This study demonstrates that embedded sensors within protective fabrics can more fully characterize liquid repellency while simultaneously detecting the hazardous substance. The liquid repellency of oleophobic textiles was detected in-situ using differential planar microwave resonator structures. A differential split ring resonator was designed with resonant responses at 4.4 and 4.6 GHz with a sensitivity of 50 MHz per unit ε. Fabrics were rendered oleophobic by dip-coating. The liquid repellency was monitored in-situ using droplets of heptane, octane, decane, dodecane, and water. Wetting transitions and droplet evaporation were identified in real time. The 4.4 GHz resonance peak's shift was used to measure the liquid repellency, whereas the 4.6 GHz resonator monitored the liquid's vapor as it absorbed into a gas-sensitive elastomer. The microwave response was tracked over 10 h every 15 s, and this transient data could identify the liquids based on their wetting and evaporation rates. Such sensors could be readily embedded in oleophobic textiles and enhance personal protective equipment.

Effect of Terminal Modifications on the Adsorption and Assembly of hIAPP(20-29).

The assembly of peptides and proteins into nanoscale amyloid fibrils via formation of intermolecular ß-sheets not only plays an important role in the development of degenerative diseases but also represents a promising approach for the synthesis of functional nanomaterials. In many biological and technological settings, peptide assembly occurs in the presence of organic and inorganic interfaces with different physicochemical properties. In an attempt to dissect the relative contributions of the different molecular interactions governing amyloid assembly at interfaces, we here present a systematic study of the effects of terminal modifications on the adsorption and assembly of the human islet amyloid polypeptide fragment hIAPP(20-29) at organic self-assembled monolayers (SAMs) presenting different functional groups (cationic, anionic, polar, or hydrophobic). Using a selection of complementary in situ and ex situ analytical techniques, we find that even this well-defined and comparatively simple model system is governed by a rather complex interplay of electrostatic interactions, hydrophobic interactions, and hydrogen bonding, resulting in a plethora of observations and dependencies, some of which are rather counterintuitive. In particular, our results demonstrate that terminal modifications can have tremendous effects on peptide adsorption and assembly dynamics, as well as aggregate morphology and molecular structure. The effects exerted by the terminal modifications can furthermore be modulated in nontrivial ways by the physicochemical properties of the SAM surface. Therefore, terminal modifications are an important factor to consider when conducting and comparing peptide adsorption and aggregation studies and may represent an additional parameter for guiding the assembly of peptide-based nanomaterials.

Adsorption and Fibrillization of Islet Amyloid Polypeptide at Self-Assembled Monolayers Studied by QCM-D, AFM, and PM-IRRAS.

Aggregation and fibrillization of human islet amyloid polypeptide (hIAPP) plays an important role in the development of type 2 diabetes mellitus. Understanding the interaction of hIAPP with interfaces such as cell membranes at a molecular level therefore represents an important step toward new therapies. Here, we investigate the fibrillization of hIAPP at different self-assembled alkanethiol monolayers (SAMs) by quartz crystal microbalance with dissipation monitoring (QCM-D), atomic force microscopy (AFM), and polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS). We find that hydrophobic interactions with the CH3-terminated SAM tend to retard hIAPP fibrillization compared to the carboxylic acid-terminated SAM where attractive electrostatic interactions lead to the formation of a three-dimensional network of interwoven fibrils. At the hydroxyl- and amino-terminated SAMs, fibrillization appears to be governed by hydrogen bonding between the peptide and the terminating groups which may even overcome electrostatic repulsion. These results thus provide fundamental insights into the molecular mechanisms governing amyloid assembly at interfaces.

Self-Assembly, Dynamics, and Polymorphism of hIAPP(20-29) Aggregates at Solid-Liquid Interfaces.

The misfolding and subsequent assembly of proteins and peptides into insoluble amyloid structures play important roles in the development of numerous diseases. The dynamics of self-assembly and the morphology of the resulting aggregates critically depend on various environmental factors and especially on the presence of interfaces. Here, we show in detail how the presence of surfaces with different physicochemical properties influences the assembly dynamics and especially the aggregate morphology of hIAPP(20-29), an amyloidogenic fragment of the peptide hormone human islet amyloid polypeptide (hIAPP), which is involved in the development of type 2 diabetes. Time-lapse atomic force microscopy is employed to study the assembly dynamics of hIAPP(20-29) and the morphology of the resulting aggregates in bulk solution as well as at hydrophilic and hydrophobic model surfaces. We find that the presence of hydrophilic mica surfaces promotes fibrillation when compared with the assembly in bulk solution and results in a more pronounced polymorphism. Three fibrillar species are found to coexist on the mica surface, that is, straight, coiled, and ribbon-like fibrils, whereas only the straight and coiled fibrils are observed in bulk solution after comparable incubation times. In addition, the straight and coiled fibrils assembled at the mica surface have significantly different dimensions compared with those assembled in bulk solution. The three fibrillar species found on the mica surface most likely form independently by lateral association of arbitrary numbers of protofibrils with about 2 nm height. On hydrophobic hydrocarbon surfaces, fibrillation is retarded but not completely suppressed, in contrast to previous observations for full-length hIAPP(1-37). Our results show that peptide-surface interactions may induce diverse, peptide-specific alterations of amyloid assembly dynamics and fibrillar polymorphism. They may therefore contribute to a deeper understanding of the molecular processes that govern amyloid aggregation at different surfaces.