title: Did α-Synuclein and Glucocerebrosidase Coevolve? Implications for Parkinson's Disease.
abstract: Mutations in the GBA1 gene are associated with increased risk of Parkinson's disease, and the protein produced by the gene, glucocerebrosidase, interacts with α-synuclein, the protein at the center of the disease etiology. One possibility is that the mutations disrupt a beneficial interaction between the proteins, and a beneficial interaction would imply that the proteins have coevolved. To explore this possibility, a correlated mutation analysis has been performed for all 72 vertebrate species where complete sequences of α-synuclein and glucocerebrosidase are known. The most highly correlated pair of residue variations is α-synuclein A53T and glucocerebrosidase G115E. Intriguingly, the A53T mutation is a Parkinson's disease risk factor in humans, suggesting the pathology associated with this mutation and interaction with glucocerebrosidase might be connected. Correlations with β-synuclein are also evaluated. To assess the impact of lowered species number on accuracy, intra and inter-chain correlations are also calculated for hemoglobin, using mutual information Z-value and direct coupling analyses.
authors.affiliation: Laboratory of Structural Biophysics, NHLBI, NIH, Bethesda, Maryland, United States of America.
authors.forename: James M
authors.initials: JM
authors.lastname: Gruschus
mesh_terms: D019943:Amino Acid Substitution; D019143:Evolution, Molecular; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D020125:Mutation, Missense; D010300:Parkinson Disease / Q000235:genetics*; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein; D005962:Glucosylceramidase