Synphilin-1A: an aggregation-prone isoform of synphilin-1 that causes neuronal death and is present in aggregates from alpha-synucleinopathy patients.
alpha-Synucleinopathies are a group of neurological disorders characterized by the presence of intracellular inclusion bodies containing alpha-synuclein. We previously demonstrated that synphilin-1 interacts with alpha-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 alpha-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 alpha-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 alpha-synucleinopathies and also provide important insights into the role of inclusion bodies in neurodegenerative disorders.
Eyal
Allon
A
Department of Pharmacology, The B. Rappaport Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel.
Szargel
Raymonde
R
Avraham
Eyal
E
Liani
Esti
E
Haskin
Joseph
J
Rott
Ruth
R
Engelender
Simone
S
D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death; D002460:Cell Line; D003001:Cloning, Molecular; D003062:Codon; D005091:Exons; D006801:Humans; D007668:Kidney; D020961:Lewy Body Disease / Q000235:genetics; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000473:pathology*; D010300:Parkinson Disease / Q000235:genetics*; D020033:Protein Isoforms / Q000502:physiology; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
D002352:Carrier Proteins; D003062:Codon; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C118958:SNCAIP protein, human; D051844:alpha-Synuclein