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New gene mutation identified in common type of dementia

ST. PAUL, MN — Researchers have identified a new gene mutation linked to frontotemporal dementia, according to a study published in the July 10, 2007 issue of Neurology®, the medical journal of the American Academy of Neurology.

Frontotemporal dementia, one form of which is known as Pick’s disease, involves progressive shrinking of the areas of the brain that control behavior and language. Symptoms include language problems and personality changes, often with inappropriate social behavior. Unlike Alzheimer’s disease dementia, the disease does not affect memory in the early stages. The genetic form of the disease is rare; most cases occur randomly.

“We are hopeful that this finding will help us better understand how this disease works and eventually help us develop new therapies for the disease,” said study author Amalia Bruni, MD, of the Regional Neurogenetic Centre in Lamezia Terme, Italy.

The researchers discovered a new mutation in the gene named progranulin in an extended family in southern Italy. The genealogy of this family has been reconstructed for 15 generations, going back to the 16th century; 36 family members have had frontotemporal dementia. For this study, DNA tests were conducted on 70 family members, including 13 people with the disease. “This is an important result that we pursued for more than 10 years,” said study co-author Ekaterina Rogaeva, PhD, with the Centre for Research in Neurodegenerative Diseases at the University of Toronto.

The mutation identified in this study is in a gene on chromosome 17. The mutation leads to a loss of progranulin, a protein growth factor that helps brain cells survive. The mutation causes only half of the protein to be produced, because only one copy of the gene is active. Production of too much progranulin has been associated with cancer.

The new gene mutation was found in nine of those family members with the disease and 10 people who are currently too young to have the symptoms of the disease. But four people with the disease did not have the gene mutation. Bruni noted that these four people belong to a branch of the family with the disease in at least three generations. “These results are intriguing, since the family has two genetically distinct diseases that appear almost identical,” said Bruni.

The Italian family had no cases with two copies of the mutated gene. “We would have expected to see cases with two copies of the mutated gene, especially since this family shares much of the same genetic material, as there have been at least five marriages between first cousins over the years,” Bruni said. “It’s possible that loss of both copies of the progranulin gene leads to the death of embryos, and that’s why there were no cases with two copies of the mutated gene.”

“Another intriguing aspect in this Italian family is the variable age at onset, which ranged from 35 to 87 years in the family members who inherited the same mutation. Our future research will try to identify the modifying factors responsible for the severity of the disorder,” said Rogaeva.

Rogaeva says their studies will also try to identify the second gene responsible for dementia in this family.

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The study was supported by grants from the Canadian Institutes of Health Research, Howard Hughes Medical Institute, Canada Foundation for Innovation, Japan-Canada and Canadian Institutes of Health Research Joint Health Research Program, Parkinson Society of Canada, W. Garfield Weston Fellows, Japanese Society for the Promotion of Science, National Institute on Aging Intramural Program, Italian Ministry of Health, and the Calabria Regional Health Department.

The American Academy of Neurology, an association of more than 20,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer’s disease, epilepsy, Parkinson’s disease, and multiple sclerosis.

For more information about the American Academy of Neurology, visit http://www.aan.com.

Contacts:

Angela Babb
ababb@aan.com
651-695-2789

Robin Stinnett
rstinnett@aan.com
651-695-2763

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July 10, 2007 Posted by | Alberta, Alzheimers, Baltimore, Barcelona, Bethesda, Calabria Regional Health Department, Calgary, Canadian Institutes of Health Research, Cancer, Chromosome 17, Epilepsy, Genes, Genetic, Genetic Link, Genetics, Global, Global Health Vision, Global News, Howard Hughes Medical Institute, Italy, Japanese Society for the Promotion of Science, Joint Health Research Program, Lamezia Terme, Multiple Sclerosis, Neurodegenerative Diseases, News, News Australia, News Canada, News Israel, News Italy, News Jerusalem, News Switzerland, News UK, News US, News USA, Ottawa, Parkinson Society of Canada, Parkinson's, Pick's Disease, Progranulin, Protein Growth Factor, Research, RSS, RSS Feed, Stroke, The American Academy of Neurology, Toronto, University of Toronto, Virginia, W. Garfield Weston Fellows, WASHINGTON, Washington DC, Washington DC City Feed, World News | Leave a comment

Tracing Parkinson’s lethal mechanism

Contact: Erin Doonan
edoonan@cell.com
617-397-2802
Cell Press

In the vast majority of Parkinson’s disease (PD) patients, the disorder arises not because of a genetic defect, but because some external insult triggers the death of dopamine-producing neurons. Now, researchers have reported progress in understanding the mechanism underlying that death, which they say suggests a new treatment pathway.

In both mice and human patients, the researchers have found evidence that neurons die because of a crippling of a particular protective enzyme that eliminates potentially damaging “reactive oxygen species” normally generated in the cell’s power plants, called mitochondria.

David Park, of the Ottawa Health Research Institute, and colleagues published their findings in the July 5, 2007 issue of the journal Neuron, published by Cell Press.

The researchers studied the mechanism of PD using a mouse model of the disease, in which a mitochondria-affecting toxin called MPTP is used to produce Parkinson’s-like brain pathology. In earlier studies, they had found that MPTP activates protein-snipping enzymes called calpains in mitochondria. They also found evidence that calpains, in turn, activate a cellular switch called Cdk5. The question, however, was how this abnormal activation ultimately kills neurons.

In their new studies, the researchers analyzed neurons to determine that Cdk5 regulates yet another enzyme called Prx2. This enzyme is known as a peroxidase and acts to render harmless the chemically active reactive oxygen species that are produced inside mitochondria in the process of generating energy for the cell.

Specifically, the researchers found that treating neurons with MPTP activates Cdk5 to switch off Prx2. What’s more, they found that activating Prx2 in MPTP-treated mice prevented the loss of dopamine-producing neurons. And they experimentally demonstrated that the action of Cdk5 on Prx2 “plays a pivotal role” in the neuronal damage from MPTP.

Importantly, the researchers discovered evidence that the loss of Prx2 activity also plays a role in human PD. They found reduced Prx2 activity in brain tissue from PD patients.

“These findings provide a mechanistic link of how a mitochondrial damaging agent, through calpain-mediated Cdk5 activation and downregulation of an important antioxidant enzyme, can increase oxidative load, leading ultimately to death,” concluded the scientists.

“Taken together, our findings suggest that strategies to modulate Prx2 activity serve as beneficial targets for treatment of PD,” they concluded. “This is of particular importance since Cdk5 is thought to have normal beneficial roles in neurons and modulating a relevant downstream target rather than Cdk5 directly may be a better therapeutic strategy with regard to this pathway.”

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The researchers include Dianbo Qu, Juliet Rashidian, Matthew P. Mount, Hossein Aleyasin, Mohammad Parsanejad, Arman Lira, Emdadul Haque, Yi Zhang, Steve Callaghan, Mireille Daigle, Maxime W.C. Rousseaux, Ruth S. Slack, Paul R. Albert, John M. Woulfe, and David S. Park of University of Ottawa, Ottawa, Ontario, Canada; Inez Vincent of University of British Columbia, Vancouver, British Columbia, Canada.

This work was partially supported by the Parkinson’s Disease Foundation and the Parkinson’s Society of Canada (D.Q.) and the Heart and Stroke Foundation (J.R., H.A.) and by funds from the Canadian Institutes of Health Research, the Parkinson’s Society Canada, the Parkinson’s Disease Foundation, the Parkinson’s Research Consortium, the US army, and the Heart and Stroke Foundation of Ontario (D.S.P.).

Qu et al.: “Role of Cdk5-Mediated Phosphorylation of Prx2 in MPTP Toxicity and Parkinson’s Disease.” Publishing in Neuron 55, 37–52, July 5, 2007. DOI 10.1016/j.neuron.2007.05.033. http://www.neuron.org.

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July 5, 2007 Posted by | Alberta, Baltimore, Barcelona, Bethesda, Calgary, Complex Chronic Conditions, Genetic, Genetics, Genome, Genomic, Global, Global Health Vision, Global News, Irvine, Japan, Medical Journals, News, News Australia, News Canada, News Israel, News Jerusalem, News UK, News US, News USA, Osaka, Parkinson's, Research, Slovakia, Spain, Virginia, WASHINGTON, Washington DC, World News | 2 Comments

Coenzyme Q10 does not improve Parkinson’s disease symptoms

Contact: Alexander Storch
Alexander.Storch@neuro.med.tu-dresden.de
JAMA and Archives Journals

Small doses of the antioxidant coenzyme Q10 appear to increase blood levels of this naturally occurring compound in patients with Parkinson’s disease, but does not improve Parkinson’s disease symptoms, according to an article posted online today that will appear in the July 2007 print issue of Archives of Neurology, one of the JAMA/Archives journals.

Parkinson’s disease is a neurodegenerative disorder characterized by tremors and difficulty with walking or other movements. The biological mechanisms underlying the condition are not fully understood, but researchers suspect a malfunction of the mitochondria, parts of the cells that help convert food to energy, according to background information in the article. Coenzyme (CoQ10), an antioxidant sold as a dietary supplement, is also involved in mitochondrial processes. “Because of these functions, CoQ10 has attracted attention concerning neuroprotective actions in neurodegenerative disorders linked to mitochondrial defects or oxidative [oxygen-related] stress, such as Huntington’s disease and Parkinson’s disease,” the authors write. Previous studies indicate that high doses of CoQ10 (1,200 milligrams) may slow the deterioration associated with Parkinson’s disease.

Alexander Storch, M.D., of the Technical University of Dresden, Germany, and colleagues conducted a randomized clinical trial of a 300-milligram dose of CoQ10 in 131 patients with Parkinson’s disease who did not have changes in motor functions and were on stable treatment for their condition. Those assigned to the treatment group took 100 milligrams of CoQ10 three times daily for three months, followed by a two-month “washout” period. The researchers assessed Parkinson’s disease symptoms before treatment began, each month during treatment and again after the washout period. Blood tests were performed at the beginning of the study, after three months of treatment and after the washout period.

A total of 106 patients completed the full three months of the study—55 in the CoQ10 group and 51 in the placebo group. The compound was well tolerated overall, and the percentage of patients who experienced adverse effects—including viral infection, diarrhea and hearing loss—did not differ between the two groups. Blood levels of CoQ10 increased in the treatment group from an average of 0.99 milligrams per liter to an average of 4.46 milligrams per liter after three months.

“Although we demonstrated a significant increase in plasma levels of CoQ10 toward levels observed with high doses of standard CoQ10 formulations in Parkinson’s disease and other disorders, our study failed to show improvement of Parkinson’s disease symptoms and did not meet its primary or secondary end points,” which were changes on scales that measured Parkinson’s disease symptoms and their effects on physical and mental functioning, the authors write. “Our study further demonstrated that 300 milligrams per day of nanoparticular CoQ10 is safe and well tolerated in patients with Parkinson’s disease already taking various antiparkinsonian medications.”

“Since we did not find symptomatic effects of CoQ10 in Parkinson’s disease, our study does not support the hypothesis that restoring the impaired energy metabolism of the diseased dopaminergic neurons leads to symptomatic benefits in Parkinson’s disease,” the authors conclude. “Future studies will need to explore the protective effects of CoQ10 at the highest effective dose (equivalent to about 2,400 milligrams per day of a standard formulation) over a long treatment period and in a large cohort of patients both sufficient to clearly define the protective potential of this compound in Parkinson’s disease.”

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(Arch Neurol. 2007;64:(doi:10.1001/archneur.64.7.nct60005). Available pre-embargo to the media at http://www.jamamedia.org.)

Editor’s Note: This study was supported by a grant from the Deutsche Parkinson-Vereinigung eV (German Parkinson Association), Neuss, Germany, and MSE Pharmazeutika GmbH, Bad Homburg, Germany. The co-enzyme Q10 and matching placebo were formulated and packaged without charge by MSE Pharmazeutika. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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May 15, 2007 Posted by | Global, Global Health Vision, Global News, JAMA, Neurology, News, News Australia, News Canada, News UK, News US, Parkinson's | Leave a comment

UCI launches effort to develop patient-specific stem cell lines

UC Irvine neurobiologist Hans Keirstead and his research team today launched a project to develop stem cell lines that genetically match human patients. These lines would allow scientists to better study conditions ranging from diabetes to Parkinson’s disease, and they would provide the basis for potential patient-specific stem cell treatments.

Contact: Jennifer Fitzenberger
jfitzen@uci.edu
949-824-3969
University of California – Irvine

May 14, 2007 Posted by | Global, Global Health Vision, Global News, Irvine, News, News Australia, News Canada, News UK, News US, Parkinson's, Stem Cells, University of California, Washington DC | Leave a comment