title: Differential aggregation properties of alpha-synuclein isoforms.
abstract: Pathologic aggregation of α-synuclein is a central process in the pathogenesis of Parkinson's disease. The α-synuclein gene (SNCA) encodes at least 4 different α-synuclein isoforms through alternative splicing (SNCA140, SNCA126, SNCA112, SNCA98). Differential expression of α-synuclein isoforms has been shown in Lewy body diseases. In contrast to the canonical α-synuclein isoform of 140 amino acid residues (SNCA140), which has been investigated in detail, little is known about the properties of the 3 alternative isoforms. We have investigated the aggregation properties of all 4 isoforms in cultured cells and analyzed fibril-formation of 3 isoforms (SNCA140, SNCA126, and SNCA98) in vitro by electron microscopy. Each of the 3 alternative isoforms aggregates significantly less than the canonical isoform SNCA140. Electron microscopy showed that SNCA140 formed the well-known relatively straight fibrils while SNCA126 formed shorter fibrils, which were arranged in parallel fibril bundles and SNCA98 formed annular structures. Expression analysis of α-synuclein isoforms in different human brain regions demonstrated low expression levels of the alternative isoforms in comparison to the canonical SNCA140 isoform. These findings demonstrate that α-synuclein isoforms differ qualitatively and quantitatively in their aggregation properties. The biological consequences of these findings remain to be explored in vitro and in vivo.
authors.affiliation: Department of Neurology, University of Kiel, Kiel, Germany.
authors.forename: May
authors.initials: M
authors.lastname: Bungeroth
authors.affiliation: Department of Neurology, University of Kiel, Kiel, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Appenzeller
authors.affiliation: Department of Neurology, University of Kiel, Kiel, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Regulin
authors.affiliation: Leibniz-Institute for Atherosclerosis Research, University of Münster, Münster, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Völker
authors.affiliation: Institute of Biochemistry, University of Kiel, Kiel, Germany.
authors.forename: Inken
authors.initials: I
authors.lastname: Lorenzen
authors.affiliation: Institute of Biochemistry, University of Kiel, Kiel, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Grötzinger
authors.affiliation: Department of Neurology, University of Kiel, Kiel, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Pendziwiat
authors.affiliation: Department of Neurology, University of Kiel, Kiel, Germany. Electronic address: g.kuhlenbaeumer@neurologie.uni-kiel.de.
authors.forename: Gregor
authors.initials: G
authors.lastname: Kuhlenbäumer
mesh_terms: D000595:Amino Acid Sequence; D001921:Brain / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000235:genetics*; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D066329:Protein Aggregates; D020033:Protein Isoforms; D051844:alpha-Synuclein
keywords: Aggregation; Alpha-synuclein; Isoforms; Parkinson