Tau phosphorylation by GSK-3β promotes tangle-like filament morphology

Background

Neurofibrillary tangles (NFTs) are intraneuronal aggregates associated with several neurodegenerative diseases including Alzheimer's disease. These abnormal accumulations are primarily comprised of fibrils of the microtubule-associated protein tau. During the progression of NFT formation, disperse and non-interacting tau fibrils become stable aggregates of tightly packed and intertwined filaments. Although the molecular mechanisms responsible for the conversion of disperse tau filaments into tangles of filaments are not known, it is believed that some of the associated changes in tau observed in Alzheimer's disease, such as phosphorylation, truncation, ubiquitination, glycosylation or nitration, may play a role.

Results

We have investigated the effects of tau phosphorylation by glycogen synthase kinase-3β (GSK-3β) on tau filaments in an in vitro model system. We have found that phosphorylation by GSK-3β is sufficient to cause tau filaments to coalesce into tangle-like aggregates similar to those isolated from Alzheimer's disease brain.

Conclusion

These results suggest that phosphorylation of tau by GSK-3β promotes formation of tangle-like filament morphology. The in vitro cell-free experiments described here provide a new model system to study mechanisms of NFT development. Although the severity of dementia has been found to correlate with the presence of NFTs, there is some question as to the identity of the neurotoxic agents involved. This model system will be beneficial in identifying intermediates or side reaction products that might be neurotoxic.     

Identification of novel high-frequency DNA methylation changes in breast cancer

Recent data have revealed that epigenetic alterations, including DNA methylation and chromatin structure changes, are among the earliest molecular abnormalities to occur during tumorigenesis. The inherent thermodynamic stability of cytosine methylation and the apparent high specificity of the alterations for disease may accelerate the development of powerful molecular diagnostics for cancer. We report a genome-wide analysis of DNA methylation alterations in breast cancer. The approach efficiently identified a large collection of novel differentially DNA methylated loci (approximately 200), a subset of which was independently validated across a panel of over 230 clinical samples. The differential cytosine methylation events were independent of patient age, tumor stage, estrogen receptor status or family history of breast cancer. The power of the global approach for discovery is underscored by the identification of a single differentially methylated locus, associated with the GHSR gene, capable of distinguishing infiltrating ductal breast carcinoma from normal and benign breast tissues with a sensitivity and specificity of 90% and 96%, respectively. Notably, the frequency of these molecular abnormalities in breast tumors substantially exceeds the frequency of any other single genetic or epigenetic change reported to date. The discovery of over 50 novel DNA methylation-based biomarkers of breast cancer may provide new routes for development of DNA methylation-based diagnostics and prognostics, as well as reveal epigenetically regulated mechanism involved in breast tumorigenesis.     

Population genetics,demographic and evolutionary history of the Dudley’s lousewort (Pedicularis dudleyi), a rare redwood forest specialist

Pedicularis dudleyi (Dudley’s Lousewort, Orobanchaceae) is an extremely rare plant endemic to the redwood forests of Central California. Until recently, the species was known only from three extant natural populations. However, in 2019, one of those populations was described as a novel species (P. rigginsiae D.J. Keil) based on morphological and ecological data leaving only two populations described as P. dudleyi. While little is known about the past distribution of the species, historical records have led to speculation that the species was once more widespread and may have suffered from habitat destruction as a result of widespread logging during the early twentieth century. We utilized a combination of ddRAD SNP and Sanger sequencing data to: (1) Test the morphological hypothesis that P. rigginsiae is distinct from P. dudleyi; (2) Describe the genetic diversity and population structure of P. dudleyi and; (3) Test the hypothesis that the species underwent a bottleneck corresponding with increased logging of redwood forests in the early twentieth century. Our results support the recognition of P. rigginsiae as distinct from P. dudleyi, increasing the conservation priority of both species. Genetic diversity statistics and analyses of genetic structure suggest that both populations of P. dudleyi are highly differentiated from each other with one population exhibiting unexpected substructure. Finally, demographic modeling supports a scenario where the contemporary rarity of the species is explained by a recent bottleneck.

     

Agricultural Landscape Transformation Needed to Meet Water Quality Goals in the Yahara River Watershed of Southern Wisconsin

Ecosystems - Balancing agricultural production with other ecosystem services is a vexing challenge. The Yahara River watershed in southern Wisconsin is a place where tensions among farmers,...     

Potential Facilitation Between a Commensal and a Pathogenic Microbe in a Wildlife Disease

We assessed the potential for microbial interactions influencing a well-documented host–pathogen system. Mycoplasma agassizii is the known etiological agent of upper respiratory tract disease in Mojave desert tortoises (Gopherus agassizii), but disease in wild animals is extremely heterogeneous. For example, a much larger proportion of animals harbor M. agassizii than those that develop disease. With the availability of a new quantitative PCR assay for a microbe that had previously been implicated in disease, Pasteurella testudinis, we tested 389 previously collected samples of nasal microbes from tortoise populations across the Mojave desert. We showed that P. testudinis is a common commensal microbe. However, we did find that its presence was associated with higher levels of M. agassizii among the tortoises positive for this pathogen. The best predictor of P. testudinis prevalence in tortoise populations was average size of tortoises, suggesting that older populations have higher levels of P. testudinis. The prevalence of co-infection in populations was associated with the prevalence of URTD, providing additional evidence for an indirect interaction between the two microbes and inflammatory disease. We showed that URTD, like many chronic, polymicrobial diseases involving mucosal surfaces, shows patterns of a polymicrobial etiology.

     

Body size changes in bivalves of the family Limidae in the aftermath of the end‐Triassic mass extinction: the Brobdingnag effect

Reduction in body size of organisms following mass extinctions is well‐known and often ascribed to the Lilliput effect. This phenomenon is expressed as a temporary body size reduction within surviving species. Despite its wide usage the term is often loosely applied to any small post‐extinction taxa. Here we assess the size of bivalves of the family Limidae (Rafineque) prior to, and in the aftermath of, the end‐Triassic mass extinction event. Of the species studied only one occurs prior to the extinction event, though is too scarce to test for the Lilliput effect. Instead, newly evolved species originate at small body sizes and undergo a within‐species size increase, most dramatically demonstrated by Plagiostoma giganteum (Sowerby) which, over two million years, increases in size by 179%. This trend is seen in both field and museum collections. We term this within‐species size increase of newly originated species in the aftermath of mass extinction, the Brobdingnag effect, after the giants that were contemporary with the Lilliputians in Swift's Gulliver's Travels. The size increase results from greater longevity and faster growth rates. The cause of the effect is unclear, although it probably relates to improved environmental conditions. Oxygen‐poor conditions in the Early Jurassic are associated with populations of smaller body size caused by elevated juvenile mortality but these are local/regional effects that do not alter the long‐term, size increase. Although temperature‐size relationships exist for many organisms (Temperature‐Size Rule and Bergmann's Rule), the importance of this is unclear here because of a poorly known Early Jurassic temperature record.     

Effect of organ site on nuclear matrix protein composition

The nuclear matrix has been linked to several important cellular functions within cells, such as DNA organization and replication, as well as regulation of gene expression. It has been reported that the nuclear matrix protein composition is altered in cells grown on different extracellular matrices in vitro. This study examined the nuclear matrix protein composition of tumors produced by MAT-LyLu (MLL) rat prostate tumor cells implanted at different organ sites within the rat. When high resolution two-dimensional gels were utilized to compare nuclear matrix protein composition to the prostate orthotopic tumor, it was found that there were distinct protein differences depending upon where the tumor grew. In particular, there were 14 proteins found in the lung, six proteins found in intramuscular, 17 proteins is the heart, and five proteins in the tail vein tumor tissue that were not present in the prostate orthotopic tumor tissue. Therefore, this study adds evidence to support that the nuclear matrix composition of a cell is dependent, at least in part, by the extracellular matrix and/or different cellular environments and may have a role in site-specific differences in tumor properties. © 1996 Wiley-Liss, Inc.