| First Author | Ageta-Ishihara N | Year | 2013 |
| Journal | Mol Brain | Volume | 6 |
| Pages | 35 | PubMed ID | 23938054 |
| Mgi Jnum | J:318132 | Mgi Id | MGI:6858365 |
| Doi | 10.1186/1756-6606-6-35 | Citation | Ageta-Ishihara N, et al. (2013) Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice. Mol Brain 6:35 |
| abstractText | 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 alpha-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 alpha-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. |
