Synphilin-1A: An Aggregation-Prone Isoform of Synphilin-1 That Causes Neuronal Death and Is Present in Aggregates from α-Synucleinopathy Patients

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-04, Vol.103 (15), p.5917-5922
• Main Authors: Eyal, Allon, Szargel, Raymonde, Avraham, Eyal, Liani, Esti, Haskin, Joseph, Rott, Ruth, Engelender, Simone
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Antibodies; Base Sequence; Biological Sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Carrier Proteins - physiology; Cell aggregates; Cell Death; Cell Line; Cloning, Molecular; Codon; Exons; HEK293 cells; Humans; Inclusion bodies; Kidney; Lewy bodies; Lewy Body Disease - genetics; Molecular Sequence Data; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - physiology; Neurological disorders; Neurology; Neurons; Neurons - pathology; Parkinson Disease - genetics; Parkinson's disease; Protein isoforms; Protein Isoforms - physiology; Start codon; Toxicity
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0509707103

α-Synucleinopathies are a group of neurological disorders characterized by the presence of intracellular inclusion bodies containing α-synuclein. We previously demonstrated that synphilin-1 interacts with α-synuclein, implying a role in Parkinson's disease. We now report the identification and characterization of synphilin-1A, an isoform of synphilin-1, which has enhanced aggregatory properties and causes neurotoxicity. The two transcripts encoding synphilin-1A and synphilin-1 originate from the SNCAIP gene but differ in both their exon organization and initial reading frames used for translation. Synphilin-1A binds to α-synuclein and induces the formation of intracellular aggregates in human embryonic kidney 293 cells, primary neuronal cultures, and human dopaminergic cells. Overexpression of synphilin-1A in neurons results in striking cellular toxicity that is attenuated by the formation of synphilin-1A inclusions, which recruit α-synuclein. Synphilin-1A is present in Lewy bodies of patients with Parkinson's disease and Diffuse Lewy Body disease, and is observed in detergent-insoluble fractions of brain protein samples obtained from Diffuse Lewy Body disease patients. These findings suggest that synphilin-1A may contribute to neuronal degeneration in α-synucleinopathies and also provide important insights into the role of inclusion bodies in neurodegenerative disorders.