Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice

Natsumi Ageta-Ishihara, Hodaka Yamakado, Takao Morita, Satoko Hattori, Keizo Takao, Tsuyoshi Miyakawa, Ryosuke Takahashi, Makoto Kinoshita

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background: In autosomal recessive early-onset Parkinsonism (PARK2), the pathogenetic process from the loss of function of a ubiquitin ligase parkin to the death of dopamine neurons remains unclear. A dominant hypothesis attributes the neurotoxicity to accumulated substrates that are exempt from parkin-mediated degradation. Parkin substrates include two septins; SEPT4/CDCrel-2 which coaggregates with -synuclein as Lewy bodies in Parkinson's disease, and its closest homolog SEPT5/CDCrel-1/PNUTL1 whose overload with viral vector can rapidly eliminate dopamine neurons in rats. However, chronic effects of pan-neural overload of septins have never been examined in mammals. To address this, we established a line of transgenic mice that express the largest gene product SEPT454kDa via the prion promoter in the entire brain. Results: Histological examination and biochemical quantification of SEPT4-associated proteins including -synuclein and the dopamine transporter in the nigrostriatal dopamine neurons found no significant difference between Sept4 Tg/+ and wild-type littermates. Thus, the hypothetical pathogenicity by the chronic overload of SEPT4 alone, if any, is insufficient to trigger neurodegenerative process in the mouse brain. Intriguingly, however, a systematic battery of behavioral tests revealed unexpected abnormalities in Sept4 Tg/+ mice that include consistent attenuation of voluntary activities in distinct behavioral paradigms and altered social behaviors. Conclusions: Together, these data indicate that septin dysregulations commonly found in postmortem human brains with Parkinson's disease, schizophrenia and bipolar disorders may be responsible for a subset of behavioral abnormalities in the patients.

Original languageEnglish
Article number35
JournalMolecular brain
Volume6
Issue number1
DOIs
Publication statusPublished - 13-08-2013

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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