Researchers at the Keck School of Medicine of the University of Southern California have uncovered structural clues about the protein linked to Parkinson disease (PD), which ultimately could lead to finding a cure for the degenerative neurologic disorder.
The alpha-synuclein (a-synuclein) protein is commonly found in the healthy human brain even though its function is not clear. The protein has been the subject of substantial Parkinson research, however, because it is a major component in the protein clumps found in Parkinson disease cases.
Unlike most proteins, which are typically rigid and occur in 1 definitive form, the alpha-synuclein protein can fold and change its structure. Researchers Tobias S Ulmer PhD and Sowmya Bekshe Lokappa PhD at the Keck School-affiliated Zilkha Neurogenetic Institute have determined that the energy difference between 2 particular alpha-synuclein structures is less than previously speculated.
Their study, to be published in the June 17 issue of The Journal of Biological Chemistry, is the first to quantify that energy difference, 1.2±0.4 kcal/mol.
"We're trying to understand the mechanisms of protein folding and misfolding," said Ulmer, the study's principal investigator and an assistant professor in the Department of Biochemistry and Molecular Biology at the Zilkha Neurogenetic Institute. "Then we can say why something is going wrong, which is essential to treating neurodegenerative disorders like Parkinson's."
If proteins misfold, they are repaired or they break down. However, when alpha-synuclein misfolds it aggregates and becomes toxic to surrounding nerve cells, Ulmer said. Understanding its folding and finding what causes aberrant folding is therefore key to determining the root cause of the disorder, he added.
To put the discovery into perspective, Ulmer compared the energy that researchers thought was needed to change the protein's structure to hurricane-force winds and the actual energy required to a light summer breeze. The experiments were conducted in 2010, measuring the energy of elongated and broken helix forms of alpha-synuclein through circular dichroism spectroscopy, fluorescence spectroscopy, and isothermal titration calorimetry.
"There may be a continuous interconversion between folded alpha-synuclein structural states that might contribute to its pathological misfolding," said Lokappa, a postdoctoral research associate at the Center for Craniofacial Molecular Biology at USC and the study's coauthor. "But we need to have even better insight into the mechanisms of protein folding and misfolding to explain what's going wrong in the brain."
Source: News Release
University of Southern California
June 15, 2011