July 3, 2013
Shape-shifting Disease Proteins May Explain Variable Appearance of Neurodegenerative Diseases, Penn Study Finds
Targeting Distinct Alpha-synuclein Strains a Potential Treatment Approach
PHILADEL
July 3, 2013
Shape-shifting Disease Proteins May Explain Variable Appearance of Neurodegenerative Diseases, Penn Study Finds
Targeting Distinct Alpha-synuclein Strains a Potential Treatment Approach
PHILADELPHIA — Neurodegenerative diseases are not all alike. Two individuals suffering from the same disease may experience very different age of onset, symptoms, severity, and constellation of impairments, as well as different rates of disease progression. Researchers in the Perelman School of Medicine at the University of Pennsylvania have shown one disease protein can morph into different strains and promote misfolding of other disease proteins commonly found in Alzheimer’s, Parkinson’s and other related neurodegenerative diseases.
Virginia M.Y. Lee, PhD, MBA, professor of Pathology and Laboratory Medicine and director of the Center for Neurodegenerative Disease Research, with co-director, John Q. Trojanowski MD, PhD, postdoctoral fellow Jing L. Guo, PhD, and colleagues, discovered that alpha-synuclein, a protein that forms sticky clumps in the neurons of Parkinson’s disease patients, can exist in at least two different structural shapes, or “strains,” when it clumps into fibrils, despite having precisely the same chemical composition.
These two strains differ in their ability to promote fibril formation of normal alpha-synuclein, as well as the protein tau, which forms neurofibrillary tangles in individuals with Alzheimer’s disease.
Importantly, these alpha-synuclein strains are not static; they somehow evolve, such that fibrils that initially cannot promote tau tangles acquire that ability after multiple rounds of “seeded” fibril formation in test tubes.
The findings appear in the July 3rd issue of Cell.
Morphed Misfolding Proteins Found In Overlapping Neurodegenerative Diseases
One possible explanation for this convergence of Alzheimer’s and Parkinson’s disease pathology in the same patient is a global disruption in protein folding. But, Guo and Lee showed that one strain of alpha-synuclein fibrils which cannot promote tau fibrillization actually evolved into another strain that could efficiently cause tau to fibrillize in cultured neurons, although both strains are identical at the amino acid sequence level. Guo and Lee called the starting conformation “Strain A,” and the evolved conformation, “Strain B.”
To figure out how A and B differ, Guo