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01.12.2014 | Research | Ausgabe 1/2014 Open Access

Molecular Autism 1/2014

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

Molecular Autism > Ausgabe 1/2014
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
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​2040-2392-5-33) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

HM and TK co-designed the study. KI and HM collected blood samples; collected, analyzed and interpreted the data and prepared the manuscript. TT and SY produced the SERT antibody. KO, HT, KY and SM collected, analyzed and interpreted the data. KN recruited participants, collected blood samples and obtained post-mortem brain samples. KJT and KM collected blood samples and undertook clinical evaluations. MT recruited participants. TS recruited participants and diagnosed ASD. TK collected, analyzed and interpreted the data and prepared the manuscript. NM analyzed and interpreted the data, and prepared the manuscript. All authors read and approved the final manuscript.



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.


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.


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.


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.
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