title: Contribution of Alanine-76 and Serine Phosphorylation in α-Synuclein Membrane Association and Aggregation in Yeasts.
abstract: In Parkinson's disease (PD), misfolded and aggregated α-synuclein protein accumulates in degenerating midbrain dopaminergic neurons. The amino acid alanine-76 in α-synuclein and phosphorylation at serine-87 and serine-129 are thought to regulate its aggregation and toxicity. However, their exact contributions to α-synuclein membrane association are less clear. We found that α-synuclein is indeed phosphorylated in fission yeast and budding yeast, the two models that we employed for assessing α-synuclein aggregation and membrane association properties, respectively. Surprisingly, blocking serine phosphorylation (S87A, S129A, and S87A/S129A) or mimicking it (S87D, S129D) altered α-synuclein aggregation in fission yeast. Either blocking or mimicking this phosphorylation increased endomembrane association in fission yeast, but only mimicking it decreased plasma membrane association in budding yeast. Polar substitution mutations of alanine-76 (A76E and A76R) decreased α-synuclein membrane association in budding yeast and decreased aggregation in fission yeast. These yeast studies extend our understanding of serine phosphorylation and alanine-76 contributions to α-synuclein aggregation and are the first to detail their impact on α-synuclein's plasma membrane and endomembrane association.
authors.affiliation: Biology Department, Lake Forest College, Box P7, 555 North Sheridan Road, Lake Forest, IL 60045, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Fiske
authors.forename: Stephanie
authors.initials: S
authors.lastname: Valtierra
authors.forename: Keith
authors.initials: K
authors.lastname: Solvang
authors.forename: Michael
authors.initials: M
authors.lastname: Zorniak
authors.forename: Michael
authors.initials: M
authors.lastname: White
authors.forename: Sara
authors.initials: S
authors.lastname: Herrera
authors.forename: Alina
authors.initials: A
authors.lastname: Konnikova
authors.forename: Rebecca
authors.initials: R
authors.lastname: Brezinsky
authors.forename: Shubhik
authors.initials: S
authors.lastname: Debburman