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Posts Tagged ‘Parkinson’s’

Blood-related genetic mechanisms found important in Parkinson’s disease

What does the genetics of blood cells have to do with brain cells related to Parkinson’s disease? From an unusual collaboration of neurologists and a pharmacologist comes the surprising answer: Genetic mechanisms at play in blood cells also control a gene and protein that cause Parkinson’s disease.

The finding, by scientists from the University of Wisconsin School of Medicine and Public Health (SMPH), Harvard University-affiliated Brigham and Women’s Hospital and the University of Ottawa, may lead to new treatments for the neurological disorder that affects as many as 1.5 million Americans.

The study is published in the Proceedings of the National Academy of Sciences Online Early Edition the week of July 21-25, 2008.

Patients with Parkinson’s disease (PD) have elevated levels of the protein called alpha-synuclein in their brains. As the protein clumps, or aggregates, the resulting toxicity causes the death of neurons that produce the brain chemical dopamine. Consequently, nerves and muscles that control movement and coordination are destroyed.

The researchers discovered that the activity of three genes that control the synthesis of heme, the major component of hemoglobin that allows red blood cells to carry oxygen, precisely matched the activity of the alpha-synuclein gene, suggesting a common switch controlling both.

The scientists then found that a protein called GATA-1, which turns on the blood-related genes, was also a major switch for alpha-synuclein expression, and that it induced a significant increase in alpha-synuclein protein. Finally, they demonstrated that a related protein — GATA-2 — was expressed in PD-vulnerable brain cells and directly controlled alpha-synuclein production.

“Very little was known previously about what turns on alpha-synuclein in brain cells and causes variations in its expression,” says Emery Bresnick, a UW-Madison professor of pharmacology who is an expert on GATA factors and their functions in blood. “Understanding how GATA factors work in the brain may provide fundamental insights into the biology of Parkinson’s disease.”

The new knowledge also may allow scientists to design therapies that keep alpha-synuclein levels within the normal range.

“Simply lowering alpha-synuclein levels by 40 percent may be enough to treat some forms of Parkinson’s disease,” says Dr. Clemens Scherzer of Harvard. “So far, researchers have focused on ways to get rid of too much ‘bad’ alpha-synuclein in Parkinson patients’ brains. Now we will be able to tackle the problem from the production site, and search for new therapies that lower alpha-synuclein production up front.”

Scherzer and Dr. Michael Schlossmacher, now at Ottawa, had independently analyzed the blood of PD patients and controls in a search for genes that were active in the disease. They both were surprised to notice large amounts of alpha-synuclein in the blood. To understand what it was doing there, Scherzer’s group used gene chip data to see whether any of the thousands of genes active in blood were linked to alpha-synuclein. They found a gene expression pattern composed of alpha-synuclein and the heme genes, one of which Bresnick had previously shown to be a direct GATA-1 target gene.

The neurologists contacted Bresnick. The UW group rapidly determined that GATA-1 directly activated the alpha-synuclein gene, and that finding led the collaborators to discover that GATA-2 is expressed in regions of the brain that are relevant to PD.

“We all were excited because we realized that GATA-2 was active in the relevant brain regions, and so there could be a connection,” says Bresnick. Together the researchers set out to examine whether common mechanisms activated alpha-synuclein transcription in both the blood and nerve cells.

The studies showed that GATA-1 and GATA-2 proteins find the alpha-synuclein gene, stick to it and then directly control it.

“This is not an indirect pathway; it is direct regulation of the gene,” says Bresnick. “This directness provides the simplest scenario for creating a therapeutic strategy.”

Bresnick, Schlossmacher and Scherzer are working with geneticists to see if possible abnormalities in the GATA-2 gene may exist in PD patients, stimulating more production of alpha-syinuclein.

“The discovery of the link between GATA proteins and the alpha-synuclein gene is like finding a long-sought-after molecular switch,” says Schlossmacher. “We were very fortunate to find in Emery Bresnick’s team the ideal partner in this endeavor.”

The family of GATA factors consists of six members, and some of them, beyond GATA-2, may also be influencing alpha-synuclein expression in the brain, adds Schlossmacher.

“Identifying these would further add to the complexity of regulating the production of the ‘bad player’ in Parkinson’s disease,” he says.

Says Bresnick, “The $10 million question will be does deregulation of the GATA mechanism in humans lead to alpha-synuclein overproduction and Parkinson’s disease.”

Source: University of Wisconsin-Madison

Cell-based therapy shows promise in patients with Parkinson’s disease

A novel cell therapy using retinal pigment epithelial (RPE) cells attached to tiny gelatin bead microcarriers implanted in the brain can improve the symptoms of patients with moderate to advanced Parkinson’s disease (PD).

Rush University Medical Center neurosurgeon Dr. Roy A. E. Bakay and colleagues from Emory University, Atlanta found the therapy Spheramine was well-tolerated and patients experienced improvement in Parkinsonian symptoms (tremor, rigidity, slowness of movements, and impaired balance and coordination.) These findings were presented at the Annual Meeting of the American Association of Neurological Surgeons in Chicago on April 28, 2008. … Continue Reading »

Different mutations in single gene suggest Parkinson’s is primarily an inherited genetic disorder

Two new international studies by researchers at the Mayo Clinic site in Florida are rounding out the notion that Parkinson’s disease is largely caused by inherited genetic mutations that pass through scores of related generations over hundreds, if not thousands of years. These genetic influences, which can be small but additive, or large and causative, overturn common beliefs that the neurodegenerative disease mostly occurs in a random fashion or is due to undetermined environmental factors.

These latest studies bring the total of number of disease-related mutations in an as yet poorly understood gene, leucine-rich repeat kinase 2 (LRRK2), to seven, all of which are linked, either weakly or strongly, to typical, late onset development of Parkinson’s disease in people around the world. One mutation (R1628P) doubles the risk of Parkinson’s disease in ethnic Chinese, according to a study published on Wednesday, April 16, 2008 in the online edition of the Annals of Neurology. The second study, published April 15 in Neurology, demonstrates that another very rare mutation (R1441C), found in people on three continents, increases risk by more than 10-fold. … Continue Reading »

Blood urate levels associated with the progression of Parkinson’s disease

Higher blood levels of the compound urate, a salt derived from uric acid that is associated with gout, may be associated with a slower progression of Parkinson’s disease, according to an article posted online today that will appear in the June 2008 print issue of Archives of Neurology, one of the JAMA/Archives journals.

Urate is a powerful antioxidant that circulates at high levels in the human bloodstream, according to background information in the article. It may serve as one of the body’s major defenses against oxidative stress, or damage to cells caused by nitrogen and oxygen. Oxidative stress may contribute to the loss of brain cells that produce dopamine, leading to Parkinson’s disease and other neurodegenerative disorders. … Continue Reading »

Identification of dopamine ‘mother cells’ could lead to future Parkinson’s treatments

‘Mother cells’ which produce the neurons affected by Parkinson’s disease have been identified by scientists, according to new research published in the journal Glia.

The new discovery could pave the way for future treatments for the disease, including the possibility of growing new neurons, and the cells which support them, in the lab. Scientists hope these could then be transplanted into patients to counteract the damage caused by Parkinson’s.

The new study focuses on dopaminergic neurons – brain cells which produce and use the chemical dopamine to communicate with surrounding neurons. The researchers found that these important neurons are created when a particular type of cell in the embryonic brain divides during the early stages of brain development in the womb. … Continue Reading »

Pieces coming together in Parkinson’s, cholesterol puzzle

In 2006, University of North Carolina at Chapel Hill researchers published a study that found people with low levels of LDL cholesterol are more likely to have Parkinson’s disease than people with high LDL levels.

But that study could not answer the question of whether low LDL (low-density lipoprotein) levels were present in study participants before they were diagnosed with Parkinson’s, or if they developed low LDL levels after being diagnosed.

Now a follow-up study led by UNC researchers in collaboration with colleagues in Virginia, Hawaii and Japan has found that low LDL levels were present in a group of men of Japanese ancestry long before these men were diagnosed with Parkinson’s. … Continue Reading »

Uterine stem cells create new neurons that can curb Parkinson’s disease

The injection of uterine stem cells trigger growth of new brain cells in mice with Parkinson’s disease, Yale School of Medicine researchers report in an abstract presented at the 2008 Society for Gynecologic Investigation (SGI) Annual Scientific Meeting held March 26-29 in San Diego, California.

“Previously, we were able to coax these multipotent stem cells to differentiate into cartilage cells,” said lead author Hugh S. Taylor, M.D., professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine and section chief of Reproductive Endocrinology and Infertility at Yale School of Medicine. “Now we have found that we can turn uterine stem cells into neurons that can boost dopamine levels and partially correct the problem of Parkinson’s disease.” … Continue Reading »

Therapeutic cloning treats Parkinson’s disease in mice

Research led by investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) has shown that therapeutic cloning, also known as somatic-cell nuclear transfer (SCNT), can be used to treat Parkinson’s disease in mice. The study’s results are published in the March 23 online edition of the journal Nature Medicine.For the first time, researchers showed that therapeutic cloning or SCNT has been successfully used to treat disease in the same subjects from whom the initial cells were derived. While this current work is in animals, it could have future implications as this method may be an effective way to reduce transplant rejection and enhance recovery in other diseases and in other organ systems. … Continue Reading »