Oddershede Skipper (bluedoctor7)

The benzdiimidazole NAB2 rescues α-synuclein-associated trafficking defects associated with early onset Parkinson's disease in a Nedd4-dependent manner. Despite identification of E3 ubiquitin ligase Nedd4 as a putative target of NAB2, its molecular mechanism of action has not been elucidated. As such, the effect of NAB2 on Nedd4 activity and specificity was interrogated through biochemical, biophysical, and proteomic analyses. NAB2 was found to bind Nedd4 (KDapp = 42 nM), but this binding is side chain mediated and does not alter its conformation or ubiquitination kinetics in vitro. Nedd4 co-localizes with trafficking organelles, and NAB2 exposure did not alter its co-localization. Ubiquitin enrichment coupled proteomics revealed that NAB2 stimulates ubiquitination of trafficking-associated proteins, most likely through modulating the substrate specificity of Nedd4, providing a putative protein network involved in the NAB2 mechanism and revealing trafficking scaffold protein TFG as a Nedd4 substrate.Oxytosis was first described over 30 years ago in nerve cells as a non-excitotoxic pathway for glutamate-induced cell death. The key steps of oxytosis, including glutathione depletion, lipoxygenase activation, reactive oxygen species accumulation, and calcium influx, were identified using a combination of chemical and genetic tools. A pathway with the same characteristics as oxytosis was identified in transformed fibroblasts in 2012 and named ferroptosis. Importantly, the pathophysiological changes seen in oxytosis and ferroptosis are also observed in multiple neurodegenerative diseases as well as in the aging brain. This led to the hypothesis that this pathway could be used as a screening tool to identify novel drug candidates for the treatment of multiple age-associated neurological disorders, including Alzheimer's disease (AD). Using this approach, we have identified several AD drug candidates, one of which is now in clinical trials, as well as new target pathways for AD.Protein degradation is mediated by an expansive and complex network of protein modification and degradation enzymes. Matching degradation enzymes with their targets and determining globally which proteins are degraded by the proteasome or lysosome/vacuole have been a major challenge. Furthermore, an integrated view of protein degradation for cellular pathways has been lacking. Here, we present an analytical platform that combines systematic gene deletions with quantitative measures of protein turnover to deconvolve protein degradation pathways for Saccharomyces cerevisiae. The resulting turnover map (T-MAP) reveals target candidates of nearly all E2 and E3 ubiquitin ligases and identifies the primary degradation routes for most proteins. We further mined this T-MAP to identify new substrates of ER-associated degradation (ERAD) involved in sterol biosynthesis and to uncover regulatory nodes for sphingolipid biosynthesis. The T-MAP approach should be broadly applicable to the study of other cellular processes, including mammalian systems.In visual areas of primates, neurons activate in parallel while the animal is engaged in a behavioral task. In this study, we examine the structure of the population code while the animal performs delayed match-to-sample tasks on complex natural images. The macaque monkeys visualized two consecutive stimuli that were either the same or different, while being recorded with laminar arrays across the cortical depth in cortical areas V1 and V4. We decode correct choice behavior from neural populations of simultaneously recorded units. Utilizing decoding weights, we divide neurons into most informative and less informative and show that most informative neurons in V4, but not in V1, are more strongly synchronized, coupled, and correlated than less informative neurons. Because neurons are divided into two coding pools according to their coding preference, in V4, but not in V1, spiking synchrony, coupling, and correlations within the c