title: Sept4, a component of presynaptic scaffold and Lewy bodies, is required for the suppression of alpha-synuclein neurotoxicity.
abstract: In Parkinson disease (PD), alpha-synuclein aggregates called Lewy bodies often involve and sequester Septin4 (Sept4), a polymerizing scaffold protein. However, the pathophysiological significance of this phenomenon is unclear. Here, we show the physiological association of Sept4 with alpha-synuclein, the dopamine transporter, and other presynaptic proteins in dopaminergic neurons; mice lacking Sept4 exhibit diminished dopaminergic neurotransmission due to scarcity of these presynaptic proteins. These data demonstrate an important role for septin scaffolds in the brain. In transgenic mice that express human alpha-synuclein(A53T) (a mutant protein responsible for familial PD), loss of Sept4 significantly enhances neuropathology and locomotor deterioration. In this PD model, insoluble deposits of Ser129-phosphorylated alpha-synuclein(A53T) are negatively correlated with the dosage of Sept4. In vitro, direct association with Sept4 protects alpha-synuclein against self-aggregation and Ser129 phosphorylation. Taken together, these data show that Sept4 may be involved in PD as a dual susceptibility factor, as its insufficiency can diminish dopaminergic neurotransmission and enhance alpha-synuclein neurotoxicity.
authors.affiliation: Biochemistry and Cell Biology Unit, HMRO, Kyoto University Graduate School of Medicine, Yoshida Konoe, Sakyo, Kyoto 606-8501, Japan. ihara@kuhp.kyoto-u.ac.jp
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamasaki
authors.forename: Akari
authors.initials: A
authors.lastname: Hagiwara
authors.forename: Ai
authors.initials: A
authors.lastname: Tanigaki
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kitano
authors.forename: Rie
authors.initials: R
authors.lastname: Hikawa
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tomimoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Noda
authors.forename: Masashi
authors.initials: M
authors.lastname: Takanashi
authors.forename: Hideo
authors.initials: H
authors.lastname: Mori
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyakawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Kinoshita
mesh_terms: D000161:Acoustic Stimulation / Q000379:methods; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D017729:Presynaptic Terminals / Q000378:metabolism*; D013216:Reflex, Startle / Q000502:physiology; D058112:Septins; D012694:Serine / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D003598:Cytoskeletal Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D016708:Synaptophysin; D051844:alpha-Synuclein; D012694:Serine; D020558:GTP Phosphohydrolases; C492027:SEPTIN4 protein, human; D058112:Septins; D004298:Dopamine