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Parkinsons Disease

Parkinsons Disease

Parkinsons Disease

Description
 Parkinson"s disease (PD) is a slowly progressive disorder of the brain that affects movement, muscle control, and balance. It is characterized by shaking (tremor) and difficulty with walking.

Who is at Risk?
 Parkinson"s disease affects about 3% of Americans over 65 years old. Experts estimate that this percentage could double in the next 30 to 40 years. The average age of onset of Parkinson"s disease is 55. About 10% of Parkinson"s cases are in people younger than 40 years old. Some research indicates that men may face up to twice the risk as women. One study suggested that the disease also progresses more rapidly in men than women. Older women seem to be more at risk for gait disturbance and men for rigidity and tremor. People with siblings or parents who developed Parkinson"s at a younger age are at higher risk for Parkinson"s disease. African- and Asian-Americans have a lower risk than European-Americans. Increasing fatness in middle age was associated with a higher risk of PD in a 2002 study.
Sources: University of Maryland Medical Center, A.D.A.M., Inc.

TSRI Scientists Describe how Chemical Turns Progenitor Stem Cells into Bone Cells
 A group of TSRI researchers, directed by Professor Peter G. Schultz, Ph.D. have described how a small synthetic molecule called "purmorphamine" causes a type of stem cell to selectively differentiate into adult bone cells. Purmorphamine, or a similar compound that has the same effect, may have significant clinical value someday for treating the bone-weakening disease osteoporosis. Purmorphamine works by activating a signaling pathway inside the progenitor cells known as "hedgehog signaling." Hedgehog signaling is involved in the development of a number of cell types other than bone cells, including cells in the central nervous system that are lost in the course of neurodegenerative diseases like Parkinson"s. The discovery that purmorphamine works through hedgehog opens up the possibility that small molecules like purmorphamine might be useful in the development of new medicines for the treatment of peripheral nerve damage or Parkinson"s disease.

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Researchers Identify a Possible Drug Target for Slowing Progression of Parkinson"s Disease
 TSRI Assistant Professor Bruno Conti, Ph.D. studies Neuroimmunology, with an emphasis on the central modulation of immune functions and the role of cytokines in neuronal activity and neurodegeneration. He also investigates the role of mitochondrial uncoupling proteins (UCP"s) in age related diseases like Alzheimer"s and Parkinson"s.

The UCP"s influence the production of free radicals, one of the main mediators of cellular damage. To investigate the role of UCP2 in neuroprotection, Conti and his colleagues generated transgenic mice overexpressing UCP2 in cathecholaminergic neurons that are selectively lost in Parkinson"s disease by placing mouse UCP2 under the control of the tyrosine hydroxylase promoter (TH-UCP2). TH-UCP2 mice have a two-fold elevation of UCP2 expression and a marked reduction of free radicals formation in the catecholaminergic neurons in the substantia nigra and in the stratium. Furthermore, TH-UCP2 mice also showed neuroprotection in a mouse model of Parkinson"s disease indicating that UCP2 may represent a drug target for slowing progression of Parkinson"s disease. Studies aimed at identifying molecules and means to elevate endogenous synthesis and activation of UCP2 are currently being undertaken.

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Scientists Discover Small Molecule That Generates Neurons From Adult Stem Cells
 A group of scientists from The Scripps Research Institute and the Salk Institute for Biological Studies have uncovered a synthetic small molecule that generates functional neurons from adult neural stem cells. The molecule, named neuropathiazol, selectively and potently induces neuronal differentiation of neural stem or progenitor cells. The results of this study may ultimately help in the development of future small molecule therapeutics that could stimulate the regeneration of neurons in patients suffering from neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, or brain injuries. The study was led by Sheng Ding, Ph.D., an assistant professor in the Scripps Research Department of Chemistry and The Skaggs Institute for Chemical Biology. Co-authors included TSRI investigator Peter G. Schultz, Ph.D. Stem cells have huge potential in medicine because they have the ability to differentiate into many different cell types - potentially providing doctors with the ability to produce cells that have been permanently lost by a patient. For instance, the damage of neurodegenerative diseases like Parkinson's, in which dopaminergic neurons in the brain are lost, may be ameliorated by regenerating neurons. However bright the promise of this type of therapy, many barriers must be overcome before stem cells can be used in medicine. Scientists have yet to understand the natural signaling mechanisms that control stem cell fate and to develop ways to manipulate these controls.

The research team led by Ding has been taking a discovery approach to finding small molecules that can control stem cell fate. Previously, the scientists reported discoveries of various small molecules that can turn embryonic stem cells into neurons or cardiac muscle cells; turn mesenchymal stem cells into bone cells; and induce a cell to undergo dedifferentiation, moving cells backwards developmentally from its current state to form its own precursor cell. As part of this effort, Ding and his colleagues have created extensive chemical and genomic libraries. In fact, their combinatorial chemical library contains more than 100,000 discrete and diverse bioactive small molecules, and high throughput screening uses various automated assays to search such large numbers of substances for a specific activity. For the current study, the researchers tested tens of thousands of small molecules in the process of identifying neuropathiazol, which they found can highly selectively turn more than 90 percent of primary adult hippocampal neural progenitors into neurons in tissue culture. The researchers believe this study provides an important step forward, opening new avenues to understanding how to control neural stem cell fate.

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Focusing On Parkinsons Disease Research
One of Scripps Florida senior director of drug discovery Philip LoGrasso, Ph.D.'s major targets in drug discovery is the c-jun-N-terminal kinase 3 (JNK3), pronounced Junk. JNK3 signaling, an important contributor to stress-induced apoptosis (programmed cell death), has been shown to play a significant role in neuronal survival. As such, JNK3 is a highly viable target for drugs to treat neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and stroke. LoGrasso and his colleagues (he has 19 people in his laboratory) are focused primarily on Parkinson's disease. They're going after a target that isn't getting as much effort in the industry, but that could benefit thousands of patients. Parkinson's disease is the second most prevalent neurodegenerative disease after Alzheimer's. It affects at least a million people in the United States with more than 50,000 new cases diagnosed annually. It kills around 15,000 patients a year.

In contrast to the existing therapies for Parkinson's, which treat only symptoms, LoGrasso's program is aimed at preventing neurodegeneration - which is where JNK3 comes in. One of three isoforms - various forms of a protein with relatively small differences - JNK3 is expressed in the nervous system and in the heart. Previous studies have showed that disrupting the neural-specific Jnk3 gene (but not Jnk1 or Jnk2 isoforms) made mice highly resistant to neuron damage from the neurotransmitter glutamate. These studies suggest that JNK3 may have a preferential role in stress-induced neuronal apoptosis. The idea is highly attractive: stop JNK3 and you might stop the death of neurons. Ultimately, LoGrasso hopes to have a molecule that could do just that in the next three to five years - an ambitious goal - after which time it could enter the drug approval process. Right now, his team is testing candidate compounds in animal models for Parkinson's disease, and he has several new papers in the works on JNK3, a kinase that he believes has multiple potential applications:. JNK1 inhibition could also work in diabetes; and JNK3 and JNK1 inhibition could work very well in congestive heart failure, heart attack and stroke. JNK3 is just starting to hit the literature and the laboratory.

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Scripps Research Findings May Help in Development of New Class of Parkinson's Treatments
Scientists from The Scripps Research Institute have determined the structure of an adenosine receptor that plays a critical role in a number of important physiological processes including pain, breathing, and heart function. The findings could lead to the development of a new class of therapeutics for treating numerous neurological disorders, including Parkinson's and Huntington disease. The scientists, led by Scripps Research scientist and professor Raymond Stevens, Ph.D., are developing a robust platform for studying human G protein-coupled receptor structure and function. This work lays a strong foundation for understanding drug-receptor interactions. The scientists expect to continue their work and develop a deep understanding as to how drugs interact with the broader class. The findings—and their future research—could one day lead to the development of a novel class of therapeutics with improved pharmaceutical properties."

The new study defined the structure of the human A 2A adenosine receptor—sometimes referred to as the "caffeine receptor"—which falls in the larger family of G protein-coupled receptors (GPCR). Stevens and his colleagues had previously determined the structure of the β2-adrenergic G protein-coupled receptor with multiple ligands. The big question then was— was it going to be another 10 years until they got the next new receptor? The answer was 'no.' It took less than a year to determine this new structure. Their expectation is that even more will come out in the next few years. Because of the importance of GPCRs to health and medicine and previous lack of knowledge about their structure, the Stevens lab's 2007 research solved the structure of the β2-adrenergic G protein-coupled receptor and was selected as one of the top 10 breakthroughs of the year by Science magazine.

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