title: The A53T mutation is key in defining the differences in the aggregation kinetics of human and mouse α-synuclein.
abstract: Despite a 95% sequence similarity, the aggregation of human and mouse α-synuclein is remarkably different, as the human form is slower than the mouse form in forming fibrils but is associated with Parkinson's disease in both humans and transgenic mice. Here, the amino acid code underlying these differences is investigated by comparing the lag times, growth rates, and secondary structure propensities of a systematic series of eight human-mouse chimeras. Fluorescence analysis of these variants shows that the A53T substitution dominates the growth kinetics, while the lag phase is affected by a combination of the A53T and S87N substitutions. The secondary structure propensities derived from an NMR chemical shift analysis of the monomeric forms of the human-mouse variants enable us to establish a link between the changes in the conformational properties in the region of position 53 upon mutation and the corresponding changes in growth rates. These results suggest that the presence of an alanine residue at position 53 may be an evolutionary adaptation to minimize Parkinson's disease in humans and indicates that effective drug development efforts may be directed to target this N-terminal region of the sequence.
authors: Department of Chemistry and Chemical Biology, Rutgers University, 610 Taylor Road, Piscataway, New Jersey 08854, United States.
authors: Lijuan
authors: L
authors: Kang
authors: Kuen-Phon
authors: KP
authors: Wu
authors: Michele
authors: M
authors: Vendruscolo
authors: Jean
authors: J
authors: Baum
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D006801:Humans; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D000682:Amyloid; D051844:alpha-Synuclein