Sept4, a component of presynaptic scaffold and Lewy bodies, is required for the suppression of alpha-synuclein neurotoxicity.
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.
Ihara
Masafumi
M
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
Yamasaki
Nobuyuki
N
Hagiwara
Akari
A
Tanigaki
Ai
A
Kitano
Ayumi
A
Hikawa
Rie
R
Tomimoto
Hidekazu
H
Noda
Makoto
M
Takanashi
Masashi
M
Mori
Hideo
H
Hattori
Nobutaka
N
Miyakawa
Tsuyoshi
T
Kinoshita
Makoto
M
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*
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