title: Conserved C-terminal charge exerts a profound influence on the aggregation rate of α-synuclein.
abstract: α-Synuclein (α-syn) is the major component of filamentous Lewy bodies found in the brains of patients diagnosed with Parkinson's disease (PD). Recent studies demonstrate that, in addition to the wild-type sequence, α-syn is found in several modified forms, including truncated and phosphorylated species. Although the mechanism by which the neuronal loss in PD occurs is unknown, aggregation and fibril formation of α-syn are considered to be key pathological features. In this study, we analyze the rates of fibril formation and the monomer-fibril equilibrium for eight disease-associated truncated and phosphorylated α-syn variants. Comparison of the relative rates of aggregation reveals a strong monotonic relationship between the C-terminal charge of α-syn and the lag time prior to the observation of fibril formation, with truncated species exhibiting the fastest aggregation rates. Moreover, we find that a decrease in C-terminal charge shifts the equilibrium to favor the fibrillar species. An analysis of these findings in the context of linear growth theories suggests that the loss of the charge-mediated stabilization of the soluble state is responsible for the enhanced aggregation rate and increased extent of fibril fraction. Therefore, C-terminal charge is kinetically and thermodynamically protective against α-syn polymerization and may provide a target for the treatment of PD.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA.
authors.forename: Katerina
authors.initials: K
authors.lastname: Levitan
authors.forename: David
authors.initials: D
authors.lastname: Chereau
authors.forename: Samuel I A
authors.initials: SI
authors.lastname: Cohen
authors.forename: Tuomas P J
authors.initials: TP
authors.lastname: Knowles
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Fink
authors.forename: John P
authors.initials: JP
authors.lastname: Anderson
authors.forename: Jason M
authors.initials: JM
authors.lastname: Goldstein
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Millhauser
mesh_terms: D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation; D055503:Protein Multimerization; D017384:Sequence Deletion; D055672:Static Electricity; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D051844:alpha-Synuclein