Sept4, a Component of Presynaptic Scaffold and Lewy Bodies, Is Required for the Suppression of α-Synuclein Neurotoxicity

Masafumi Ihara, Nobuyuki Yamasaki, Akari Hagiwara, Ai Tanigaki, Ayumi Kitano, Rie Hikawa, Hidekazu Tomimoto, Makoto Noda, Masashi Takanashi, Hideo Mori, Nobutaka Hattori, Tsuyoshi Miyakawa, Makoto Kinoshita

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)519-533
Number of pages15
JournalNeuron
Volume53
Issue number4
DOIs
Publication statusPublished - 15-02-2007

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Synucleins
Lewy Bodies
Parkinson Disease
Synaptic Transmission
Septins
Dopamine Plasma Membrane Transport Proteins
Proteins
Dopaminergic Neurons
Mutant Proteins
Transgenic Mice
Phosphorylation
Brain

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Ihara, M., Yamasaki, N., Hagiwara, A., Tanigaki, A., Kitano, A., Hikawa, R., ... Kinoshita, M. (2007). Sept4, a Component of Presynaptic Scaffold and Lewy Bodies, Is Required for the Suppression of α-Synuclein Neurotoxicity. Neuron, 53(4), 519-533. https://doi.org/10.1016/j.neuron.2007.01.019
Ihara, Masafumi ; Yamasaki, Nobuyuki ; Hagiwara, Akari ; Tanigaki, Ai ; Kitano, Ayumi ; Hikawa, Rie ; Tomimoto, Hidekazu ; Noda, Makoto ; Takanashi, Masashi ; Mori, Hideo ; Hattori, Nobutaka ; Miyakawa, Tsuyoshi ; Kinoshita, Makoto. / Sept4, a Component of Presynaptic Scaffold and Lewy Bodies, Is Required for the Suppression of α-Synuclein Neurotoxicity. In: Neuron. 2007 ; Vol. 53, No. 4. pp. 519-533.
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abstract = "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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Ihara, M, Yamasaki, N, Hagiwara, A, Tanigaki, A, Kitano, A, Hikawa, R, Tomimoto, H, Noda, M, Takanashi, M, Mori, H, Hattori, N, Miyakawa, T & Kinoshita, M 2007, 'Sept4, a Component of Presynaptic Scaffold and Lewy Bodies, Is Required for the Suppression of α-Synuclein Neurotoxicity', Neuron, vol. 53, no. 4, pp. 519-533. https://doi.org/10.1016/j.neuron.2007.01.019

Sept4, a Component of Presynaptic Scaffold and Lewy Bodies, Is Required for the Suppression of α-Synuclein Neurotoxicity. / Ihara, Masafumi; Yamasaki, Nobuyuki; Hagiwara, Akari; Tanigaki, Ai; Kitano, Ayumi; Hikawa, Rie; Tomimoto, Hidekazu; Noda, Makoto; Takanashi, Masashi; Mori, Hideo; Hattori, Nobutaka; Miyakawa, Tsuyoshi; Kinoshita, Makoto.

In: Neuron, Vol. 53, No. 4, 15.02.2007, p. 519-533.

Research output: Contribution to journalArticle

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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

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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