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Molecular Autism
Published in: Molecular Autism 1/2014

Open Access 01-12-2014 | Research

N-ethylmaleimide-sensitive factor interacts with the serotonin transporter and modulates its trafficking: implications for pathophysiology in autism

Authors: Keiko Iwata, Hideo Matsuzaki, Taro Tachibana, Koji Ohno, Saori Yoshimura, Hironori Takamura, Kohei Yamada, Shinsuke Matsuzaki, Kazuhiko Nakamura, Kenji J Tsuchiya, Kaori Matsumoto, Masatsugu Tsujii, Toshirou Sugiyama, Taiichi Katayama, Norio Mori

Published in: Molecular Autism | Issue 1/2014

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Abstract

Background

Changes in serotonin transporter (SERT) function have been implicated in autism. SERT function is influenced by the number of transporter molecules present at the cell surface, which is regulated by various cellular mechanisms including interactions with other proteins. Thus, we searched for novel SERT-binding proteins and investigated whether the expression of one such protein was affected in subjects with autism.

Methods

Novel SERT-binding proteins were examined by a pull-down system. Alterations of SERT function and membrane expression upon knockdown of the novel SERT-binding protein were studied in HEK293-hSERT cells. Endogenous interaction of SERT with the protein was evaluated in mouse brains. Alterations in the mRNA expression of SERT (SLC6A4) and the SERT-binding protein in the post-mortem brains and the lymphocytes of autism patients were compared to nonclinical controls.

Results

N-ethylmaleimide-sensitive factor (NSF) was identified as a novel SERT-binding protein. NSF was co-localized with SERT at the plasma membrane, and NSF knockdown resulted in decreased SERT expression at the cell membranes and decreased SERT uptake function. NSF was endogenously co-localized with SERT and interacted with SERT. While SLC6A4 expression was not significantly changed, NSF expression tended to be reduced in post-mortem brains, and was significantly reduced in lymphocytes of autistic subjects, which correlated with the severity of the clinical symptoms.

Conclusions

These data clearly show that NSF interacts with SERT under physiological conditions and is required for SERT membrane trafficking and uptake function. A possible role for NSF in the pathophysiology of autism through modulation of SERT trafficking, is suggested.
Appendix
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Metadata
Title
N-ethylmaleimide-sensitive factor interacts with the serotonin transporter and modulates its trafficking: implications for pathophysiology in autism
Authors
Keiko Iwata
Hideo Matsuzaki
Taro Tachibana
Koji Ohno
Saori Yoshimura
Hironori Takamura
Kohei Yamada
Shinsuke Matsuzaki
Kazuhiko Nakamura
Kenji J Tsuchiya
Kaori Matsumoto
Masatsugu Tsujii
Toshirou Sugiyama
Taiichi Katayama
Norio Mori
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Autism / Issue 1/2014
Electronic ISSN: 2040-2392
DOI
https://doi.org/10.1186/2040-2392-5-33

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