[paula_w]

SPOTLIGHT PLACED ON PUTAMEN PUZZLE IN PARKINSON AND PURE AUTONOMIC FAILURE June 2008

CHICAGO-Patients with pure autonomic failure (PAF) may lose as many dopaminergic neurons in the substantia nigra as do people with Parkinson disease (PD), a new study presented here in April at the AAN annual meeting suggests.
The investigators combined PET scanning with CSF catechol measurements in more than two dozen patients and two postmortem samples, finding that PAF patients lost as many dopaminergic neurons in the substantia nigra as patients with PD, yet somehow managed to retain normal dopamine activity in the putamen.
A leading dysautonomia researcher characterized the findings as surprising, difficult to understand, and in need of confirmation by others.
Where is the dopamine in the putamen coming from? asked Horacio Kaufmann, MD, professor of neurology, medicine, and pediatrics and the F. B. Axelrod Professor of Dysautonomia Research at New York University School of Medicine.
In an interview with Neurology Today, the lead author of the study conceded that his findings are puzzling, and admitted .......


http://tinyurl.com/6fucap

[RLSmi]

on the thread started by Paula containing really perceptive email comments from Greg Wasson. The subject is the lousy design of clinical trials on PD treatments, especially the poor choices of endpoints.

Drs. Safer and Kaufmann in this Neurology Today article are positing that at least three disorders, Pure Autonomic Failure, Parkinson's Disease and Dementia with Lewy Bodies, each with distinct clinical features, are different manifestations of the same disease entity, Synucleopathy, and each one is distinct only in the anatomic location of the neurons where the formation of the alpha synuclein-containing Lewy bodies occurs.

Research should concentrate on what those neurons have in common that result in the overproduction and/or aggregation of alpha synuclein protein. I'm convinced that's where the key to this puzzle is to be found.

Robert

p.s. when i tried to go back to the link a second time, i got a server error message that told me to insert "b." in front of "tinyurl" in the browser URL address box, then click on "Go" to bring up the journal. it worked.

[ZucchiniFlower]

worth a repost!


Researchers reverse Parkinson's symptoms in animal models

CAMBRIDGE, Mass. (June 22, 2006) — Statistics for neurological disorders are grim. More than a million Americans suffer from Parkinson's disease alone—a number that is expected to soar over the next few decades as the population ages. No current therapies alter the fundamental clinical course of the condition.

Now, scientists at Whitehead Institute, in collaboration with colleagues at several research centers, including the University of Missouri's School of Biological Sciences, have identified a key biological pathway that, when obstructed, causes Parkinson's symptoms. Even more importantly, they have figured out how to repair that pathway and restore normal neurological function in certain animal models.

"For the first time we've been able to repair dopaminergic neurons, the specific cells that are damaged in Parkinson's disease," says Whitehead Member and Howard Hughes Medical Institute Investigator Susan Lindquist, senior author on the paper that will be published June 22 online in Science.

“This gives a whole new direction for understanding what's been going wrong in these patients, and for considering much better strategies for treating people,” says Antony Cooper from the University of Missouri, Kansas City.

In 2003, researchers in the Lindquist lab described using yeast cells as "living test tubes" in which they could study Parkinson's. A paper published in Science reported that when a Parkinson's-related protein called alpha-synuclein was over-expressed in these cells, clumps of misshapen proteins gathered near the membrane, and in many cases the cells either became sick or died.

Aaron Gitler and Anil Cashikar, postdoctoral researchers in the Lindquist lab, decided to follow up on these results by asking a simple question: Is it possible to rescue these cells when an over-expression of alpha-synuclein would normally make them sick?

They began with an array of yeast cells in which each cell over-expressed one particular gene. This array, prepared by scientists at the Harvard Institute of Proteomics, covers the entire yeast genome. All cells were also infected with alpha-synuclein. They reasoned that if they identified genes whose over-expression rescued a cell, that would tell them something about how alpha-synuclein made the cell sick in the first place.

Most of the proteins that they identified pointed to a pathway that involves two cellular organelles, the endoplasmic reticulum (ER) and the Golgi. The ER is the cell's protein factory, where proteins assume their requisite shapes. Once a protein has properly folded, it is trafficked over to the Golgi, where it is fine-tuned and further prepared for its designated task.

Working with Antony Cooper from the University of Missouri, Kansas City, Lindquist's team demonstrated that when alpha-synuclein becomes mutated and clumps at the cell surface, it manages to drag away a protein that helps transport between the ER and the Golgi. Proteins are blocked from navigating this crucial route, and the cell dies.

This isn't just a general toxic effect caused by any misfolded protein. It is specific to alpha-synuclein, the protein associated with Parkinson's Disease.

"All this was done in yeast," says Gitler. "Our next goal was to find out what this told us about actual neurons."

If mutations of alpha-synuclein dragged the ER/Golgi transport protein away from doing its job, as the yeast research indicated, then cell death might be averted simply by increasing the levels of this transport protein. Working with colleagues at University of Pennsylvania, University of Alabama, and Purdue University, the consortium tested this hypothesis in the fruit fly, C. elegans worm, and in neurons culled from rats-all of which had alpha-synuclein-induced Parkinson's symptoms. In every case, symptoms were reversed by increasing levels of this transport protein.

"We tried this a number of different ways, from creating transgenic animals that naturally over-expressed this protein, to injecting a copy of the gene for this transport protein into the neurons through a gene-therapy technique," says Gitler. "In all cases the results were the same. Cell death ceased, and the neurons were restored to normal health."

"Protein folding problems are universal, so we hoped we could use these simple model organisms to study something as deeply complex as neurodegenerative disease," says Lindquist, who is also a professor of biology at MIT. "Most people thought we were crazy. But we now not only have made progress in understanding this dreadful disease, but we have a new platform for screening pharmaceuticals."

These findings also help explain why biopsies from Parkinson's patients indicate stress in the ER of dopaminergic neurons.

"This gives a whole new direction for understanding what's been going wrong in these patients, and for considering much better strategies for treating people," says Cooper.

The work was supported by the National Institutes of Health.



June 22, 2006

\http://www.wi.mit.edu/news/archives/2006/sl_0622.html

[ZucchiniFlower]

Science 27 July 2007:
Vol. 317. no. 5837, pp. 516 - 519
DOI: 10.1126/science.1143780


Sirtuin 2 Inhibitors Rescue {alpha}-Synuclein-Mediated Toxicity in Models of Parkinson's Disease

Tiago Fleming Outeiro,1,2 Eirene Kontopoulos,3* Stephen M. Altmann,2* Irina Kufareva,4 Katherine E. Strathearn,5 Allison M. Amore,2 Catherine B. Volk,5 Michele M. Maxwell,2 Jean-Christophe Rochet,5 Pamela J. McLean,1,2 Anne B. Young,2 Ruben Abagyan,4 Mel B. Feany,3 Bradley T. Hyman,1,2 Aleksey G. Kazantsev2{dagger}

The sirtuins are members of the histone deacetylase family of proteins that participate in a variety of cellular functions and play a role in aging. We identified a potent inhibitor of sirtuin 2 (SIRT2) and found that inhibition of SIRT2 rescued {alpha}-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson's disease. Genetic inhibition of SIRT2 via small interfering RNA similarly rescued {alpha}-synuclein toxicity. Furthermore, the inhibitors protected against dopaminergic cell death both in vitro and in a Drosophila model of Parkinson's disease. The results suggest a link between neurodegeneration and aging.

http://www.sciencemag.org/cgi/conten...i;317/5837/516