TY - JOUR
T1 - Sept4, a Component of Presynaptic Scaffold and Lewy Bodies, Is Required for the Suppression of α-Synuclein Neurotoxicity
AU - Ihara, Masafumi
AU - Yamasaki, Nobuyuki
AU - Hagiwara, Akari
AU - Tanigaki, Ai
AU - Kitano, Ayumi
AU - Hikawa, Rie
AU - Tomimoto, Hidekazu
AU - Noda, Makoto
AU - Takanashi, Masashi
AU - Mori, Hideo
AU - Hattori, Nobutaka
AU - Miyakawa, Tsuyoshi
AU - Kinoshita, Makoto
N1 - Funding Information:
We thank R. Takahashi, Y. Mizuno, T. Iwatsubo, and Y. Kaziro for suggestions and encouragements; V.M.-Y. Lee and J.Q. Trojanowski for the generous gift of α-synuclein A53T transgenic mice; D.R. Borchelt for the prion promoter; S. Yamada for the generation of Sept4-Tg mice; A. Kinoshita, Y. Fukazawa, and R. Shigemoto for technical advice; and A. Khundakar for critical reading of our manuscript. This study was supported in part by Special Coordination Funds for Promoting Science and Technology; Grants-in-Aid from MEXT of Japan, PRESTO from JST, and Takeda Science Foundation (to M.K.); a postdoctoral fellowship from JSPS; and a Grant from the Ichiro Kanehara Memorial Foundation (to M.I.).
PY - 2007/2/15
Y1 - 2007/2/15
N2 - In Parkinson disease (PD), α-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 α-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 α-synucleinA53T (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 α-synucleinA53T are negatively correlated with the dosage of Sept4. In vitro, direct association with Sept4 protects α-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 α-synuclein neurotoxicity.
AB - In Parkinson disease (PD), α-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 α-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 α-synucleinA53T (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 α-synucleinA53T are negatively correlated with the dosage of Sept4. In vitro, direct association with Sept4 protects α-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 α-synuclein neurotoxicity.
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U2 - 10.1016/j.neuron.2007.01.019
DO - 10.1016/j.neuron.2007.01.019
M3 - Article
C2 - 17296554
AN - SCOPUS:33846817344
SN - 0896-6273
VL - 53
SP - 519
EP - 533
JO - Neuron
JF - Neuron
IS - 4
ER -
