2013年8月
Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice
MOLECULAR BRAIN
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- 巻
- 6
- 号
- 開始ページ
- 35
- 終了ページ
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1186/1756-6606-6-35
- 出版者・発行元
- BIOMED CENTRAL LTD
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 a-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 SEPT4(54kDa) via the prion promoter in the entire brain.
Results: Histological examination and biochemical quantification of SEPT4-associated proteins including a-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.
Results: Histological examination and biochemical quantification of SEPT4-associated proteins including a-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.
- リンク情報
- ID情報
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- DOI : 10.1186/1756-6606-6-35
- ISSN : 1756-6606
- PubMed ID : 23938054
- Web of Science ID : WOS:000323154900001