According to a study from the University of Cambridge, small alterations in a protein’s sequence can significantly affects the onset of Parkinson's disease (PD). The study appears in Proceedings of the National Academy of Sciences. The protein, called alpha-synuclein (also α-synuclein), is abundant in the brain. Its exact function in the healthy brain remains unclear. In PD, alpha-synuclein is thought to play a pathogenic role, because it’s a key component of Lewy bodies, which are protein clumps that are hallmark of the disorder. The sequence of the alpha-synuclein protein contains 140 amino acids. Normally, it’s important for the smooth flow of chemical signals in the brain. For unknown reason, this protein misfolds, builds up and forms protein clusters called Lewy-bodies, leading to PD onset. This study focused on mutated forms of alpha-synuclein in individuals who had family history of PD. Some of these mutations only caused one change to the protein’s sequence. These small differences actually had a big effect on the rate of formation of fibrils. Moreover, the mutations significantly affects an amplification process termed secondary nucleation. In this process, the existing fibrils facilitate the formation of new aggregates, leading to their exponential increase and disease spread. Lead author of the study, Dr Patrick Flagmeier, said that this discovery could help comprehend why individuals with these mutations have higher risk of developing PD. While people without mutant alpha-synuclein can also develop the disorder, the five mutations studied in this work seem to elevate its risk. The aim of the study is to determine how these alterations in the sequence of alpha-synuclein affects its behavior when it forms fibrils. The research team looked at the five mutated forms of alpha-synuclein and a standard version of the protein. To understand this, the researchers conducted lab tests in which they added each of the five mutated forms of alpha-synuclein, as well as a standard version of the protein, to samples simulating the fibril growth process at three different stages of development, and found that the mutated forms of alpha-synuclein have a big effect on the initial formation of the fibrils, and their secondary nucleation. Dr Flagmeier concluded that these small alterations in alpha-synuclein’s sequence profoundly affect microscopic steps in the aggregation process that may result in PD. Furthermore, recombinant proteins like alpha-synuclein and Recombinant Mmel1 are offered by CusAb, a professional manufacturer of biomolecules that can be used in scientific research.
