title: alpha-Synuclein is colocalized with 14-3-3 and synphilin-1 in A53T transgenic mice.
abstract: alpha-Synuclein is a major constituent of Lewy bodies, the neuropathological hallmark of Parkinson's disease (PD). Three types of alpha-synuclein mutations, A53T, A30P, and E46K, have been reported in familial PD. Wild-type alpha-synuclein accumulates at high concentrations in Lewy bodies, and this process is accelerated with mutated A53T alpha-synuclein. The accumulation of alpha-synuclein is thought to be toxic, and causes neuronal death when alpha-synuclein aggregates into protofibrils and fibrils. Lewy bodies contain not only alpha-synuclein, but also other proteins including 14-3-3 proteins and synphilin-1. 14-3-3 Proteins exist mainly as dimers and are related to intracellular signal transduction pathways. Synphilin-1 is known to interact with alpha-synuclein, promoting the formation of cytoplasmic inclusions like Lewy bodies in vitro. To investigate the colocalization of alpha-synuclein, synphilin-1, and 14-3-3 proteins, we performed immunohistochemical studies on alpha-synuclein, 14-3-3 proteins, and synphilin-1 in the brain and spinal cord of A53T transgenic mice. In homozygous mouse brains, alpha-synuclein immunoreactivity was observed in the neuronal somata and processes in the medial part of the brainstem, deep cerebellar nuclei, and spinal cord. The distribution of 14-3-3 proteins and synphilin-1 immunoreactivity was similar to that of alpha-synuclein in the homozygous mice. Double immunofluorescent staining showed that alpha-synuclein and synphilin-1 or 14-3-3 proteins were colocalized in the pons and spinal cord. These results indicate that the accumulation of mutant alpha-synuclein occurs in association with 14-3-3 proteins and synphilin-1, and may cause the sequestration of important proteins including 14-3-3 proteins and synphilin-1. The sequestration and subsequent decrease in 14-3-3 proteins and synphilin-1 levels may account for neuronal cell death.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan. yshiraka@kuhp.kyoto-u.ac.jp
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Shirakashi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kawamoto
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tomimoto
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C118958:SNCAIP protein, human; D051844:alpha-Synuclein