Differential aggregation properties of alpha-synuclein isoforms

• Published in: Neurobiology of aging Vol. 35; no. 8; pp. 1913 - 1919
• Main Authors: Bungeroth, May, Appenzeller, Silke, Regulin, Annika, Völker, Wolfgang, Lorenzen, Inken, Grötzinger, Joachim, Pendziwiat, Manuela, Kuhlenbäumer, Gregor
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2014
• Subjects: Aggregation; Alpha-synuclein; alpha-Synuclein - chemistry; alpha-Synuclein - metabolism; Amino Acid Sequence; Brain - metabolism; HEK293 Cells; Humans; Internal Medicine; Isoforms; Molecular Sequence Data; Neurology; Parkinson; Parkinson Disease - genetics; Protein Aggregates; Protein Aggregation, Pathological - metabolism; Protein Isoforms - metabolism; Aggregation; Parkinson; Alpha-synuclein; Isoforms
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2014.02.009

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.