Alpha-synuclein facilitates to form short unconventional microtubules that have a unique function in the axonal transport

Shiori Toba, Mingyue Jin, Masami Yamada, Kanako Kumamoto, Sakiko Matsumoto, Takuo Yasunaga, Yuko Fukunaga, Atsuo Miyazawa, Sakiko Fujita, Kyoko Itoh, Shinji Fushiki, Hiroaki Kojima, Hideki Wanibuchi, Yoshiyuki Arai, Takeharu Nagai, Shinji Hirotsune

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Although α-synuclein (αSyn) has been linked to Parkinson's disease (PD), the mechanisms underlying the causative role in PD remain unclear. We previously proposed a model for a transportable microtubule (tMT), in which dynein is anchored to a short tMT by LIS1 followed by the kinesin-dependent anterograde transport; however the mechanisms that produce tMTs have not been determined. Our in vitro investigations of microtubule (MT) dynamics revealed that αSyn facilitates the formation of short MTs and preferentially binds to MTs carrying 14 protofilaments (pfs). Live-cell imaging showed that αSyn co-transported with dynein and mobile βIII-tubulin fragments in the anterograde transport. Furthermore, bi-directional axonal transports are severely affected in αSyn and γSyn depleted dorsal root ganglion neurons. SR-PALM analyses further revealed the fibrous co-localization of αSyn, dynein and βIII-tubulin in axons. More importantly, 14-pfs MTs have been found in rat femoral nerve tissue, and they increased approximately 19 fold the control in quantify upon nerve ligation, indicating the unconventional MTs are mobile. Our findings indicate that αSyn facilitates to form short, mobile tMTs that play an important role in the axonal transport. This unexpected and intriguing discovery related to axonal transport provides new insight on the pathogenesis of PD.

Original languageEnglish
Article number16386
JournalScientific reports
Volume7
Issue number1
DOIs
Publication statusPublished - 01-12-2017
Externally publishedYes

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Synucleins
alpha-Synuclein
Axonal Transport
Microtubules
Dyneins
Parkinson Disease
Tubulin
Femoral Nerve
Nerve Tissue
Kinesin
Spinal Ganglia
Ligation
Axons
Neurons

All Science Journal Classification (ASJC) codes

  • General

Cite this

Toba, Shiori ; Jin, Mingyue ; Yamada, Masami ; Kumamoto, Kanako ; Matsumoto, Sakiko ; Yasunaga, Takuo ; Fukunaga, Yuko ; Miyazawa, Atsuo ; Fujita, Sakiko ; Itoh, Kyoko ; Fushiki, Shinji ; Kojima, Hiroaki ; Wanibuchi, Hideki ; Arai, Yoshiyuki ; Nagai, Takeharu ; Hirotsune, Shinji. / Alpha-synuclein facilitates to form short unconventional microtubules that have a unique function in the axonal transport. In: Scientific reports. 2017 ; Vol. 7, No. 1.
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abstract = "Although α-synuclein (αSyn) has been linked to Parkinson's disease (PD), the mechanisms underlying the causative role in PD remain unclear. We previously proposed a model for a transportable microtubule (tMT), in which dynein is anchored to a short tMT by LIS1 followed by the kinesin-dependent anterograde transport; however the mechanisms that produce tMTs have not been determined. Our in vitro investigations of microtubule (MT) dynamics revealed that αSyn facilitates the formation of short MTs and preferentially binds to MTs carrying 14 protofilaments (pfs). Live-cell imaging showed that αSyn co-transported with dynein and mobile βIII-tubulin fragments in the anterograde transport. Furthermore, bi-directional axonal transports are severely affected in αSyn and γSyn depleted dorsal root ganglion neurons. SR-PALM analyses further revealed the fibrous co-localization of αSyn, dynein and βIII-tubulin in axons. More importantly, 14-pfs MTs have been found in rat femoral nerve tissue, and they increased approximately 19 fold the control in quantify upon nerve ligation, indicating the unconventional MTs are mobile. Our findings indicate that αSyn facilitates to form short, mobile tMTs that play an important role in the axonal transport. This unexpected and intriguing discovery related to axonal transport provides new insight on the pathogenesis of PD.",
author = "Shiori Toba and Mingyue Jin and Masami Yamada and Kanako Kumamoto and Sakiko Matsumoto and Takuo Yasunaga and Yuko Fukunaga and Atsuo Miyazawa and Sakiko Fujita and Kyoko Itoh and Shinji Fushiki and Hiroaki Kojima and Hideki Wanibuchi and Yoshiyuki Arai and Takeharu Nagai and Shinji Hirotsune",
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Toba, S, Jin, M, Yamada, M, Kumamoto, K, Matsumoto, S, Yasunaga, T, Fukunaga, Y, Miyazawa, A, Fujita, S, Itoh, K, Fushiki, S, Kojima, H, Wanibuchi, H, Arai, Y, Nagai, T & Hirotsune, S 2017, 'Alpha-synuclein facilitates to form short unconventional microtubules that have a unique function in the axonal transport', Scientific reports, vol. 7, no. 1, 16386. https://doi.org/10.1038/s41598-017-15575-3

Alpha-synuclein facilitates to form short unconventional microtubules that have a unique function in the axonal transport. / Toba, Shiori; Jin, Mingyue; Yamada, Masami; Kumamoto, Kanako; Matsumoto, Sakiko; Yasunaga, Takuo; Fukunaga, Yuko; Miyazawa, Atsuo; Fujita, Sakiko; Itoh, Kyoko; Fushiki, Shinji; Kojima, Hiroaki; Wanibuchi, Hideki; Arai, Yoshiyuki; Nagai, Takeharu; Hirotsune, Shinji.

In: Scientific reports, Vol. 7, No. 1, 16386, 01.12.2017.

Research output: Contribution to journalArticle

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T1 - Alpha-synuclein facilitates to form short unconventional microtubules that have a unique function in the axonal transport

AU - Toba, Shiori

AU - Jin, Mingyue

AU - Yamada, Masami

AU - Kumamoto, Kanako

AU - Matsumoto, Sakiko

AU - Yasunaga, Takuo

AU - Fukunaga, Yuko

AU - Miyazawa, Atsuo

AU - Fujita, Sakiko

AU - Itoh, Kyoko

AU - Fushiki, Shinji

AU - Kojima, Hiroaki

AU - Wanibuchi, Hideki

AU - Arai, Yoshiyuki

AU - Nagai, Takeharu

AU - Hirotsune, Shinji

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Although α-synuclein (αSyn) has been linked to Parkinson's disease (PD), the mechanisms underlying the causative role in PD remain unclear. We previously proposed a model for a transportable microtubule (tMT), in which dynein is anchored to a short tMT by LIS1 followed by the kinesin-dependent anterograde transport; however the mechanisms that produce tMTs have not been determined. Our in vitro investigations of microtubule (MT) dynamics revealed that αSyn facilitates the formation of short MTs and preferentially binds to MTs carrying 14 protofilaments (pfs). Live-cell imaging showed that αSyn co-transported with dynein and mobile βIII-tubulin fragments in the anterograde transport. Furthermore, bi-directional axonal transports are severely affected in αSyn and γSyn depleted dorsal root ganglion neurons. SR-PALM analyses further revealed the fibrous co-localization of αSyn, dynein and βIII-tubulin in axons. More importantly, 14-pfs MTs have been found in rat femoral nerve tissue, and they increased approximately 19 fold the control in quantify upon nerve ligation, indicating the unconventional MTs are mobile. Our findings indicate that αSyn facilitates to form short, mobile tMTs that play an important role in the axonal transport. This unexpected and intriguing discovery related to axonal transport provides new insight on the pathogenesis of PD.

AB - Although α-synuclein (αSyn) has been linked to Parkinson's disease (PD), the mechanisms underlying the causative role in PD remain unclear. We previously proposed a model for a transportable microtubule (tMT), in which dynein is anchored to a short tMT by LIS1 followed by the kinesin-dependent anterograde transport; however the mechanisms that produce tMTs have not been determined. Our in vitro investigations of microtubule (MT) dynamics revealed that αSyn facilitates the formation of short MTs and preferentially binds to MTs carrying 14 protofilaments (pfs). Live-cell imaging showed that αSyn co-transported with dynein and mobile βIII-tubulin fragments in the anterograde transport. Furthermore, bi-directional axonal transports are severely affected in αSyn and γSyn depleted dorsal root ganglion neurons. SR-PALM analyses further revealed the fibrous co-localization of αSyn, dynein and βIII-tubulin in axons. More importantly, 14-pfs MTs have been found in rat femoral nerve tissue, and they increased approximately 19 fold the control in quantify upon nerve ligation, indicating the unconventional MTs are mobile. Our findings indicate that αSyn facilitates to form short, mobile tMTs that play an important role in the axonal transport. This unexpected and intriguing discovery related to axonal transport provides new insight on the pathogenesis of PD.

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