Adult male alcoholics with ASPD have abnormal emotional responsiveness to both pleasant and unpleasant stimuli relative to alcoholics without ASPD and to controls.
Prion diseases are a group of neurodegenerative diseases endemic in humans and several ruminants caused by the misfolding of native prion protein (PrP) into pathological conformations. Experimental work and the mad-cow epidemic of the 1980s exposed a wide spectrum of animal susceptibility to prion diseases, including a few highly resistant animals: horses, rabbits, pigs, and dogs/canids. The variable susceptibility to disease offers a unique opportunity to uncover the mechanisms governing PrP misfolding, neurotoxicity, and transmission. Previous work indicates that PrP-intrinsic differences (sequence) are the main contributors to disease susceptibility. Several residues have been cited as critical for encoding PrP conformational stability in prion-resistant animals, including D/E159 in dog, S167 in horse, and S174 in rabbit and pig PrP (all according to human numbering). These amino acids alter PrP properties in a variety of assays, but we still do not clearly understand the structural correlates of PrP toxicity. Additional insight can be extracted from comparative structural studies, followed by molecular dynamics simulations of selected mutations, and testing in manipulable animal models. Our working hypothesis is that protective amino acids generate more compact and stable structures in a C-terminal subdomain of the PrP globular domain. We will explore this idea in this review and identify subdomains within the globular domain that may hold the key to unravel how conformational stability and disease susceptibility are encoded in PrP.
Misfolding of the prion protein (PrP) is responsible for devastating neurological disorders in humans and other mammals. An unresolved problem in the field is unraveling the mechanisms governing PrP conformational dynamics, misfolding, and the cellular mechanism leading to neurodegeneration. The variable susceptibility of mammals to prion diseases is a natural resource that can be exploited to understand the conformational dynamics of PrP. Here we present a new fly model expressing human PrP with new, robust phenotypes in brain neurons and the eye. Using comparable attP2 insertions, we demonstrate the heightened toxicity of human PrP compared to rodent PrP along with a specific interaction with the amyloid-β peptide. Using this new model, we started to uncover the intrinsic (sequence / structure) and extrinsic (interactions) factors regulating PrP toxicity. We describe PERK and ATF4as key cellular mechanism mediating the toxicity of human PrP and uncover a key new protective activity for 4E-BP, an ATF4 transcriptional target. Lastly, mutations in human PrP (N159D, D167S, N174S) show partial protective activity, revealing its high propensity to misfold into toxic conformations.
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