379 research outputs found
Complex folding and misfolding effects of deer-specific amino acid substitutions in the β2-α2 loop of murine prion protein
The β2–α2 loop of PrPC is a key modulator of disease-associated prion protein misfolding. Amino acids that differentiate mouse (Ser169, Asn173) and deer (Asn169, Thr173) PrPC appear to confer dramatically different structural properties in this region and it has been suggested that amino acid sequences associated with structural rigidity of the loop also confer susceptibility to prion disease. Using mouse recombinant PrP, we show that mutating residue 173 from Asn to Thr alters protein stability and misfolding only subtly, whilst changing Ser to Asn at codon 169 causes instability in the protein, promotes oligomer formation and dramatically potentiates fibril formation. The doubly mutated protein exhibits more complex folding and misfolding behaviour than either single mutant, suggestive of differential effects of the β2–α2 loop sequence on both protein stability and on specific misfolding pathways. Molecular dynamics simulation of protein structure suggests a key role for the solvent accessibility of Tyr168 in promoting molecular interactions that may lead to prion protein misfolding. Thus, we conclude that ‘rigidity’ in the β2–α2 loop region of the normal conformer of PrP has less effect on misfolding than other sequence-related effects in this region
Polarizing Bubble Collisions
We predict the polarization of cosmic microwave background (CMB) photons that
results from a cosmic bubble collision. The polarization is purely E-mode,
symmetric around the axis pointing towards the collision bubble, and has
several salient features in its radial dependence that can help distinguish it
from a more conventional explanation for unusually cold or hot features in the
CMB sky. The anomalous "cold spot" detected by the Wilkinson Microwave
Anisotropy Probe (WMAP) satellite is a candidate for a feature produced by such
a collision, and the Planck satellite and other proposed surveys will measure
the polarization on it in the near future. The detection of such a collision
would provide compelling evidence for the string theory landscape.Comment: Published version. 15 pages, 8 figure
Susceptibilities of Nonhuman Primates to Chronic Wasting Disease
A species barrier may protect humans from this disease
Environmental Sources of Prion Transmission in Mule Deer
Whether transmission of the chronic wasting disease (CWD) prion among cervids requires direct interaction with infected animals has been unclear. We report that CWD can be transmitted to susceptible animals indirectly, from environments contaminated by excreta or decomposed carcasses. Under experimental conditions, mule deer (Odocoileus hemionus) became infected in two of three paddocks containing naturally infected deer, in two of three paddocks where infected deer carcasses had decomposed in situ ≈1.8 years earlier, and in one of three paddocks where infected deer had last resided 2.2 years earlier. Indirect transmission and environmental persistence of infectious prions will complicate efforts to control CWD and perhaps other animal prion diseases
Cosmic 21-cm Fluctuations as a Probe of Fundamental Physics
Fluctuations in high-redshift cosmic 21-cm radiation provide a new window for
observing unconventional effects of high-energy physics in the primordial
spectrum of density perturbations. In scenarios for which the initial state
prior to inflation is modified at short distances, or for which deviations from
scale invariance arise during the course of inflation, the cosmic 21-cm power
spectrum can in principle provide more precise measurements of exotic effects
on fundamentally different scales than corresponding observations of cosmic
microwave background anisotropies.Comment: 8 pages, 2 figure
A status report on the observability of cosmic bubble collisions
In the picture of eternal inflation as driven by a scalar potential with
multiple minima, our observable universe resides inside one of many bubbles
formed from transitions out of a false vacuum. These bubbles necessarily
collide, upsetting the homogeneity and isotropy of our bubble interior, and
possibly leading to detectable signatures in the observable portion of our
bubble, potentially in the Cosmic Microwave Background or other precision
cosmological probes. This constitutes a direct experimental test of eternal
inflation and the landscape of string theory vacua. Assessing this possibility
roughly splits into answering three questions: What happens in a generic bubble
collision? What observational effects might be expected? How likely are we to
observe a collision? In this review we report the current progress on each of
these questions, improve upon a few of the existing results, and attempt to lay
out directions for future work.Comment: Review article; comments very welcome. 24 pages + 4 appendices; 19
color figures. (Revised version adds two figures, minor edits.
Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network
BACKGROUND: Mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) cause autosomal dominant forms of Alzheimer disease (ADAD). More than 280 pathogenic mutations have been reported in APP, PSEN1, and PSEN2. However, understanding of the basic biological mechanisms that drive the disease are limited. The Dominantly Inherited Alzheimer Network (DIAN) is an international observational study of APP, PSEN1, and PSEN2 mutation carriers with the goal of determining the sequence of changes in presymptomatic mutation carriers who are destined to develop Alzheimer disease.
RESULTS: We generated a library of 98 dermal fibroblast lines from 42 ADAD families enrolled in DIAN. We have reprogrammed a subset of the DIAN fibroblast lines into patient-specific induced pluripotent stem cell (iPSC) lines. These cells were thoroughly characterized for pluripotency markers.
CONCLUSIONS: This library represents a comprehensive resource that can be used for disease modeling and the development of novel therapeutics
A single dose of the gamma-secretase inhibitor semagacestat alters the cerebrospinal fluid peptidome in humans
Background: In Alzheimer’s disease, beta-amyloid peptides in the brain aggregate into toxic oligomers and
plaques, a process which is associated with neuronal degeneration, memory loss, and cognitive decline. One
therapeutic strategy is to decrease the production of potentially toxic beta-amyloid species by the use of inhibitors
or modulators of the enzymes that produce beta-amyloid from amyloid precursor protein (APP). The failures of
several such drug candidates by lack of effect or undesired side-effects underscore the importance to monitor the
drug effects in the brain on a molecular level. Here we evaluate if peptidomic analysis in cerebrospinal fluid (CSF)
can be used for this purpose.
Methods: Fifteen human healthy volunteers, divided into three groups, received a single dose of placebo or either
140 mg or 280 mg of the γ-secretase inhibitor semagacestat (LY450139). Endogenous peptides in CSF, sampled
prior to administration of the drug and at six subsequent time points, were analyzed by liquid chromatography
coupled to mass spectrometry, using isobaric labeling based on the tandem mass tag approach for relative
quantification.
Results: Out of 302 reproducibly detected peptides, 11 were affected by the treatment. Among these, one was
derived from APP and one from amyloid precursor-like protein 1. Nine peptides were derived from proteins that
may not be γ-secretase substrates per se, but that are regulated in a γ-secretase-dependent manner.
Conclusions: These results indicate that a CSF peptidomic approach may be a valuable tool both to verify target
engagement and to identify other pharmacodynamic effects of the drug. Data are available via ProteomeXchange
with identifier PXD00307
Levels of Abnormal Prion Protein in Deer and Elk with Chronic Wasting Disease
Infected deer may pose a higher risk than elk for disease transmission
Biochemical Properties of Highly Neuroinvasive Prion Strains
Infectious prions propagate from peripheral entry sites into the central nervous system (CNS), where they cause progressive neurodegeneration that ultimately leads to death. Yet the pathogenesis of prion disease can vary dramatically depending on the strain, or conformational variant of the aberrantly folded and aggregated protein, PrPSc. Although most prion strains invade the CNS, some prion strains cannot gain entry and do not cause clinical signs of disease. The conformational basis for this remarkable variation in the pathogenesis among strains is unclear. Using mouse-adapted prion strains, here we show that highly neuroinvasive prion strains primarily form diffuse aggregates in brain and are noncongophilic, conformationally unstable in denaturing conditions, and lead to rapidly lethal disease. These neuroinvasive strains efficiently generate PrPSc over short incubation periods. In contrast, the weakly neuroinvasive prion strains form large fibrillary plaques and are stable, congophilic, and inefficiently generate PrPSc over long incubation periods. Overall, these results indicate that the most neuroinvasive prion strains are also the least stable, and support the concept that the efficient replication and unstable nature of the most rapidly converting prions may be a feature linked to their efficient spread into the CNS
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