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Mayo Clinic: Brain disorder suggests common mechanism may underlie many neurodegenerative diseases
Date:1/11/2009

, which include early-onset parkinsonism (stiffness, slowness and rigidity), depression, severe weight loss, and increasing difficulty in breathing. Once symptoms occur, typically in the patient's mid-40s, the disease is rapidly progressive and fatal.

In a subsequent study published in August 2008, the consortium reported that eight patients who died from the disease had substantial loss of neurons in the midbrain area known as the substantia nigra. They also found a molecular signature of Perry syndrome "inclusions," or clumps, of a protein known as TDP-43 which is found in patients with frontotemporal dementia or with motor neuron disease. What these clumps represent is not known, says co-author and neuropathologist Dennis Dickson, M.D. "But they are clearly a marker of the disease process in all of these disorders, suggesting a common process is perturbed," he says.

Mayo geneticists hypothesized that Perry syndrome may be caused by mutations within the same gene, even though families afflicted with this disorder are unrelated, and come from different continents. The disease is autosomal dominant, meaning that the chance of inheriting the disease is 50 percent if one parent carries a copy of a mutant gene. With the help and participation of eight families with Perry syndrome, the Mayo-led team set out to find the defective gene.

They determined that each family had one of five novel mutations in the DCTN1 gene, whose protein produces a large subunit of the dynactin complex known as p150glued. This protein is essential to the movement of cargo along the microtubule rails. "Curiously, the mutations all cluster in the p150glued cytoskeleton-associated protein glycine-rich domain and its 'GKNDG' binding motif," Dr. Farrer says. "This region acts like a parking brake, so Perry mutations in p150glued mean that this brake is affected. It would be analogous to driving that train with faulty brakes."

What amazed the researchers ar
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Contact: Kevin Punskky
punsky.kevin@mayo.edu
904-953-2299
Mayo Clinic
Source:Eurekalert

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