In so-called “shape-shifting proteins,” scientists have identified a potential reason why two people with the same neurodegenerative disease can show significantly different symptoms and at varying severities.
Writing in Cell, investigators at the University of Pennsylvania Perelman School of Medicine today show that alpha-synuclein can exist in at least two different structural forms when clumped into Parkinson’s disease-associated fibrils. These two shapes, the researchers report, differ in their ability to promote fibril formation of normal alpha-synuclein as well as tau, which forms neurofibrillary tangles in Alzheimer's disease.
Pennsylvania’s Virginia Lee, Ph.D., and her colleagues also show that these alpha-synuclein forms are not static. Some fibrils that at first cannot promote tau tangles can eventually gain the ability to do so. Dr. Lee et al. suggest that, despite having the same chemical composition, these proteins change conformation such that alpha-synuclein fibrils, which cannot promote tau fibrilization, can effectively evolve into another shape that can cause cause tau to fibrillize.
The researchers suggest that their findings could have implications for the development of therapeutics designed to target the different forms of this Parkinson’s disease-associated protein.
“What we've found opens up new areas for developing therapies, and particularly immunotherapies, for Parkinson's and other neurodegenerative diseases," Dr. Lee said in a statement.
"Distinct α-Synuclein strains differentially promote tau inclusions in neurons" appeared in Cell July 3.