Archive for July, 2009

SAN DIEGO, CA – Accumulation of the synaptic protein alpha-synuclein, resulting in the formation of aggregates called Lewy bodies in the brain, is a hallmark of Parkinson’s and other related neurodegenerative diseases. This pathology appears to spread throughout the brain as the disease progresses. Now, researchers at the University of California, San Diego School of Medicine and Konkuk University in Seoul, South Korea, have described how this mechanism works. Their findings – the first to show neuron-to-neuron transmission of alpha-synuclein – appeared recently in the Proceedings of the National Academy of Sciences.

“The discovery of cell-to-cell transmission of this protein may explain how alpha-synuclein aggregates can pass to new, healthy cells,” said first author Paula Desplats, project scientist in University of California San Diego’s Department of Neurosciences. “We demonstrated how alpha-synuclein is taken up by neighboring cells, including grafted neuronal precursor cells, a mechanism that may cause Lewy bodies to spread to different brain structures.”

This insight will impact research into stem cell therapy for Parkinson’s disease. “Our findings indicate that the stem cells used to replace lost or damaged cells in the brains of Parkinson’s disease patients are also susceptible to degeneration,” said Eliezer Masliah, MD, professor of neurosciences and pathology at University of California San Diego School of Medicine. “Knowledge of the molecular basis of the intercellular transmission of alpha-synuclein may result in improved stem-cell based therapies with long-lasting benefits, by preventing the grafted cells to uptake α-synuclein or by making them more efficient in clearing the accumulated alpha-synuclein .”

In a large proportion of Parkinson’s disease cases, the aggregation of alpha-synuclein progresses in a predictable pattern – from the lower brainstem, into the limbic system and eventually to the neocortex, the part of the brain responsible for higher level cognitive functions. The hypothesis of disease progression by neuron-to-neuron transmission of alpha-synuclein that encouraged this study was supported by findings of two separate reports in 2008. In these studies, autopsies of deceased Parkinson’s patients who had received implants of therapeutic fetal neurons 11 to 16 years prior revealed that alpha-synuclein had propagated to the transplanted neurons.

Collaborating with South Korean researcher Seung-Jae Lee, the University of California San Diego researchers first looked at neural precursor cells in culture, co-culturing them with neuronal cells expressing alpha-synuclein . After 24 to 48 hours, the aggregated alpha-synuclein was evident in the precursor cells – results suggesting cell-to-cell transmission. Using specific inhibitors, the research team also discovered that alpha-synuclein is transmitted via endocytosis, the normal process by which cells absorb proteins from the extracellular media by engulfing them within their cell membrane. Blockage of the endocytic pathway resulted in lesser accumulation of alpha-synuclein

Additionally, the researchers found that failure of the quality-control systems of the cell contributes to the observed accumulation of alpha-synuclein in recipient cells. This is due to inhibited activity of cell particles called lysosomes, which would usually degrade and remove aggregates – resulting in their increased formation.

Next, the team tested to determine if alpha-synuclein could be transmitted directly from host to grafted cells in a mouse model of Parkinson’s disease. Brains of the mouse model were grafted with fresh, healthy stem cells. Within four weeks, cells containing Lewy body-like masses were quite common, supporting the cell-to cell transmission mechanism.

- MFP Wire Services
- 7-31-2009

PITTSBURGH, PA – A new approach to statistical analysis may be better suited to study the relationship between higher “dose” of dialysis and survival time for patients with advanced kidney disease, according to an upcoming paper in the Journal of the American Society of Nephrology.

Some studies have shown longer survival times for patients receiving a higher dose of dialysis, while others show no such relationship. Thus, Christos Argyropoulos, MD, PhD (University of Pittsburgh Medical Center) and colleagues analyzed data from a large group of U.S. dialysis patients using the new statistical technique as well as conventional methods.

The “accelerated failure time” model (inspired by considerations of what happens when kidneys cease working and many unidentified toxins start building up in the patient’s bloodstream) showed longer survival times at a higher dose of dialysis, compared to no significant effect with the conventional model. Upon analysis using this technique, patient survival increased steadily along with dialysis dose, after adjustment for other risk factors (age, heart disease, diabetes, comorbid conditions, etc).

The results suggest that the conflicting results of previous studies may be related to the limitations of the statistical methods used. Small to moderately sized clinical trials may be particularly sensitive to this effect, adds Argyropoulos. “From a public health perspective, it may be reasonable to re-examine the clinical trial data with unconventional, yet scientifically valid statistical techniques and encourage relevant basic research in statistics and epidemiology to facilitate future clinical studies in this area.”

The study was limited by the lack of follow-up information on the dose of dialysis the patients received at multiple clinic visits. “Consequently, no conclusions could or should be drawn about the validity of existing national and international guidelines concerning an adequate dialysis dose,” says Argyropoulos. He also stresses that the findings cannot be generalized to non-U.S. patients.

- MFP Wire Services
- 7-31-2009

PRINCETON, NJ – Certainly there is strength in numbers, but only if those numbers can effectively communicate with one another. Now, a new study finds that administration of a novel small molecule which effectively disrupts a key bacterial communication process protects an animal host from infection. The research, published by Cell Press in a recent issue of the journal Molecular Cell, may lead to more effective treatments for bacterial infection that won’t encourage growth of treatment resistant bacteria.

Bacteria use a process called “quorum sensing” to communicate information about population density and to synchronously engage in group behaviors that promote bacterial pathogenesis. “Quorum sensing allows bacteria to collectively carry out tasks that would be unsuccessful if carried out by an individual bacterium acting alone,” explains senior study author Dr. Bonnie L. Bassler from the Howard Hughes Medical Institute and the Department of Molecular Biology at Princeton University.

During the process of quorum sensing, bacteria communicate via chemical signals called autoinducers. Autoinducers bind to receptors, called LuxR-type proteins, located inside the bacteria, or to receptors called LuxN proteins located in the bacterial membrane. In an earlier study, Dr. Bassler and colleagues discovered a class of small molecules that prevented a key autoinducer called acylhomoserine lactone from binding to LuxN. Although LuxN and LuxR are not structurally similar, Dr. Bassler’s team hypothesized that since both bind to acylhomoserine lactones, both may respond to the small molecule antagonists.

In the current study, the researchers demonstrated that the small molecule previously shown to block LuxN-type receptors is also a potent antagonist of LuxR receptors. This finding was somewhat surprising as these proteins are not evolutionarily related and exhibit vast differences in receptor localization, structure and signaling mechanisms. Importantly, the most potent antagonist protected nematode worms from quorum sensing-mediated killing by Chromobacterium violaceum, a human pathogen that frequently infects people through lacerated skin.

“Our results make a strong case and provide compelling evidence that an anti-quorum-sensing strategy is a valid alternative to traditional antibiotics and that there is merit to pursuing the clinical relevance of such strategies,” offers Dr. Bassler. The work is also significant in that treatments based on disruption of quorum sensing interfere only with bacterial signaling and not growth, potentially minimizing the sometimes devastating development of bacteria that are resistant to treatment.

- MFP Wire Services
- 7-31-2009