Friday, September 2, 2011

Alzheimer's Brains Found to Have Lower Levels of Key Protein

ScienceDaily (Sep. 1, 2011) — Researchers have found that a protein variation linked by some genetic studies to Alzheimer's disease is consistently present in the brains of people with Alzheimer's. In further biochemical and cell culture investigations, they have shown that this protein, known as ubiquilin-1, performs a critical Alzheimer's-related function: it "chaperones" the formation of amyloid precursor protein, a molecule whose malformation has been directly tied to Alzheimer's pathology.

"What we saw here is that in all 20 of the Alzheimer's brains we examined the ubiquilin-1 protein level was lower, and that's completely new," said University of Texas Medical Branch at Galveston assistant professor José Barral, co-author of a paper on the study now online in the Journal of Biological Chemistry. "Our experiments looked at the consequences of decreased ubiquilin-1, and showed that it's necessary for the proper handling of amyloid precursor protein."
APP has been a major focus of Alzheimer's investigators for almost two decades, ever since scientists identified it as the source of so-called "protein plaques," abnormal aggregations of proteins nearly always found in the brains of Alzheimer's victims. Ubiquilin-1's significance was revealed after the UTMB researchers established ubiquilin-1's status as a chaperone protein for APP.
In the origami-like folding process by which proteins arrive at their proper shape, chaperone proteins act as, well, chaperones: they bind to their client proteins and make sure they don't misbehave.
The kind of APP misbehavior Alzheimer's researchers are most concerned about is the formation of toxic aggregations of the protein or its breakdown products, both inside and outside brain cells. Through a series of biochemical and cell-culture experiments, the UTMB team was able to show that ubiquilin-1 decreased this aggregation.
"Ubiquilin-1 prevents the APP molecule from falling into a conformation it's not supposed to be in," said UTMB associate professor Darren Boehning, co-author of the Journal of Biological Chemistry paper. "This fits with a theme we're seeing across the neurodegenerative disorders and the disorders of aging -- the idea that many of these disorders are associated with decreased quality control by chaperones."
Other authors of the Journal of Biological Chemistry paper include graduate student Emily Stieren, research scientist Amina El Ayadi, graduate student Yao Xiao, graduate student Efraín Siller, Professor Andres Oberhauser and Assistant Professor Megan Landsverk of Baylor College of Medicine. The National Institutes of Health and the Jean C. and William D. Willis Neuroscience Research Endowment supported this work.

Sunday, August 28, 2011

Recent Drug Discovery and Biomarker Research Highlights

Drug discovery
1. Brain arachidonic acid cascade enzymes as therapeutic drug target for the treatment of Alzheimer’s disease
2. A real-time thallium flux HTS assay of human potassium channel opener
3. A simple assay for screening of protein kinase inhibitors in cell lysates
4. A label-free high-throughput mass spectrometry assay for rapidly screening epigenetic targets
5. A mutation in the human proteasome is associated with Nakajo-Nishimura syndrome
6. A spectrophotometric assay for conjugation of ubiquitin and ubiquitin-like proteins

1. Protein chip for diagnosis of sepsis
2. c-myb alternative splicing variants as potential biomarkers of leukemia
3. Biomarkers for the diagnosis of anorchia
4. Biomarkers for assessing therapeutic efficacy in patients with Hutchinson-Gilford progeria syndrome
5. IGF-1 as a biomarker of abdominal aortic aneurysms
6. Serum N-glycans as colorectal cancer biomarkers
7. Gene markers associated with NEO personality traits
8. Human intelligence is highly heritable and polygenic
9. Mannose 6-phosphate as a biomarker for the diagnosis of mucolipidosis Type II
10. ME-2 antigen as a biomarker for the diagnosis of endometriosis
11. Uromodulin and Kinins as biomarkers for the diagnosis of chronic allograft dysfunction
12. Micronucleus as a biomarker to screen women who are at risk of developing cervical cancer
13. Biomarkers of neuronal ceroid lipofuscinosis
14. Biomarkers to identify CKD patients in whom sodium targeting can improve blood pressure and proteinuria
15. Mitochondrial DNA copy number as a possible biomarker of pancreatic cancer
16. Biomarkers associated with higher risk of progression in lacunar strokes
17. XRCC1 SNP biomarker to predict genetic susceptibility for papillary thyroid carcinoma
18. HESRG as a specific biomarker for intracranial germinoma and embryonal carcinoma
19. Predictive biomarkers of efavirenz-based HAART-induced liver injury in HIV patients
20. Biomarker for predicting the development of cerebral vasospasm after aneurysmal subarachnoid hemorrhage

Wednesday, August 24, 2011

At last, malaria-free mosquitoes
In a study published on July 15 in PLoS Pathogens, researchers demonstrate how to genetically alter mosquitoes so they no longer transmit the Plasmodium falciparum parasite, which causes malaria in humans.
Dr. Michael Riehle and colleagues at the University of Arizona, along with partners at UC Davis, have managed to alter the mosquitoes’ genome in such a way that the Plasmodium parasite is no longer able to cause infection when ingested in malaria-infected blood. The authors explain that their genetic modification “acts like a switch that is always set to ‘on,’ leading to the permanent activity of a signaling enzyme called Akt. Akt functions as a messenger molecule in several metabolic functions, including larval development, immune response and lifespan.”
Their original intent was to alter the lifespan or growth rate of mosquitoes (Anopheles stephensi, in this case), and this genetic construct has also been shown to reduce an insect’s lifespan by up to 20%. Most importantly, this altered genetic information is passed on to later generations – if the malaria-resistant mosquitoes can be provided with additional evolutionary advantages and released into the wild (a controversial topic), they could potentially out-perform and eventually replace the malaria-infected wild mosquitoes.
The study has received a wide range of media coverage, including: