A series of dihydropyridines were identified that have an effect on the accumulation of tau, an important target in Alzheimer's disease. The dihydropyridine collection was expanded using the Hantzsch multicomponent reaction to develop preliminary structure–activity relationships.
Cataracts reduce vision in 50% of individuals over 70 years of age and are a common form of blindness worldwide. Cataracts are caused when damage to the major lens crystallin proteins causes their misfolding and aggregation into insoluble amyloids. Using a thermal stability assay, we identified a class of molecules that bind α-crystallins (cryAA and cryAB) and reversed their aggregation in vitro. The most promising compound improved lens transparency in the R49C cryAA and R120G cryAB mouse models of hereditary cataract. It also partially restored protein solubility in the lenses of aged mice in vivo and in human lenses ex vivo. These findings suggest an approach to treating cataracts by stabilizing α-crystallins.
Summary Cataracts are the leading cause of blindness in the world, currently treatable only with surgery. The molecular chaperone α ‐crystallin helps to maintain the transparency of the crystallin lens. The soluble fraction of this protein decreases with aging, a phenomenon that is associated with presbyopia and age‐related cataract. Moreover, destabilizing mutations in α ‐crystallin are associated with early onset, hereditary cataract. We hypothesized that a ligand that binds and stabilizes α ‐crystallin may prevent its aggregation, representing a strategy for preventing or even treating cataract. We developed computational and experimental high‐throughput screening techniques to identify small molecule ligands for α ‐crystallin. These molecules prevented and reversed protein aggregation and improved lens transparency when dosed to mice with cataracts. The presentation will include a discussion of the potential of the molecular chaperone α ‐crystallin as a target for therapeutic intervention in cataracts. The safety, efficacy, bioavailability, and mechanism of the active compounds will be discussed, along with considerations of how a potential pharmacological intervention might complement the existing surgical treatment paradigm.
Despite the fact that ribosomal proteins are the constituents of an organelle that is present in every cell, they show a surprising level of regulation, and several of them have also been shown to have other extra-ribosomal functions, such in replication, transcription, splicing or even ageing. This review provides a comprehensive summary of these important aspects.
Nine neurodegenerative disorders are caused by the abnormal expansion of polyglutamine (polyQ) regions within distinct proteins. Genetic and biochemical evidence has documented that the molecular chaperone, heat shock protein 70 (Hsp70), modulates polyQ toxicity and aggregation, yet it remains unclear how Hsp70 might be used as a potential therapeutic target in polyQ-related diseases. We have utilized a pair of membrane-permeable compounds that tune the activity of Hsp70 by either stimulating or by inhibiting its ATPase functions. Using these two pharmacological agents in both yeast and PC12 cell models of polyQ aggregation and toxicity, we were surprised to find that stimulating Hsp70 solubilized polyQ conformers and simultaneously exacerbated polyQ-mediated toxicity. By contrast, inhibiting Hsp70 ATPase activity protected against polyQ toxicity and promoted aggregation. These findings clarify the role of Hsp70 as a possible drug target in polyQ disorders and suggest that Hsp70 uses ATP hydrolysis to help partition polyQ proteins into structures with varying levels of proteotoxicity. Our results thus support an emerging concept in which certain kinds of polyQ aggregates may be protective, while more soluble polyQ species are toxic.
Abstract : This is a summary of research conducted on the high-G onset Air Force Research Laboratory centrifuge at Brooks City-Base TX. G-LOC and A-LOC research on the centrifuge is summarized. It was found that the G-LOC episode lasts longer than the nominal 24 sec previously described. It was found that pilot performance can be impaired up to EO sec after a G-LOC. No adverse effect of sustained acceleration was observed in Subjects who had PRK-treated eyes. There has been a proposal to eliminate the counter-pressure vest in pilots flying high- performance aircraft. Subjects reported no adverse effects of using Positive Pressure Breathing without the counter-pressure vest. The Navy's Smart Aircrew Integrated Life Support System (SAILSS) was evaluated on the centrifuge. The SAILSS is an advanced development project for the Navy with the objective of developing the next-generation aircrew life Support system. The Human Information Processing under Dynamic Environment program was evaluated on both the Brooks and Wright-Patterson AFB centrifuges.
αB-crystallin is a small heat shock protein that forms a heterooligomeric complex with αA-crystallin in the ocular lens. It is also widely distributed in tissues throughout the body and has been linked with neurodegenerative diseases such as Alzheimer’s, where it is associated with amyloid fibrils. Crystallins can form amorphous aggregates in cataracts as well as more structured amyloid-like fibrils. The arginine 120 to glycine (R120G) mutation in αB-crystallin ( Cryab -R120G) results in high molecular weight crystallin protein aggregates and loss of the chaperone activity of the protein in vitro , and it is associated with human hereditary cataracts and myopathy. Characterizing the amorphous (unstructured) versus the highly ordered (amyloid fibril) nature of crystallin aggregates is important in understanding their role in disease and important to developing pharmacological treatments for cataracts. We investigated protein secondary structure in wild-type (WT) and Cryab -R120G knock-in mutant mouse lenses using two-dimensional infrared (2DIR) spectroscopy, which has been used to detect amyloid-like fibrils in human lenses and measure UV radiation-induced changes in porcine lenses. Our goal was to compare the aggregated proteins in this mouse lens model to human lenses and evaluate the protein structural relevance of the Cryab -R120G knock-in mouse model to general age-related cataract disease. In the 2DIR spectra, amide I diagonal peak frequencies were red-shifted to smaller wavenumbers in mutant mouse lenses as compared to WT mouse lenses, consistent with an increase in ordered secondary structure. The cross peak frequency and intensity indicated the presence of amyloid in the mutant mouse lenses. While the diagonal and cross peak changes in location and intensity from the 2DIR spectra indicated significant structural differences between the wild type and mutant mouse lenses, these differences were smaller than those found in human lenses; thus, the Cryab -R120G knock-in mouse lenses contain less amyloid-like secondary structure than human lenses. The results of the 2DIR spectroscopy study confirm the presence of amyloid-like secondary structure in Cryab -R120G knock-in mice with cataracts and support the use of this model to study age-related cataract.
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