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 SEPT4 54kDa 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 language | English |
|---|---|
| Article number | 35 |
| Journal | Molecular Brain |
| Volume | 6 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 13-08-2013 |
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cellular and Molecular Neuroscience
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Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice. / Ageta-Ishihara, Natsumi; Yamakado, Hodaka; Morita, Takao; Takai, Satoko; Takao, Keizo; Miyakawa, Tsuyoshi; Takahashi, Ryosuke; Kinoshita, Makoto.
In: Molecular Brain, Vol. 6, No. 1, 35, 13.08.2013.Research output: Contribution to journal › Article
TY - JOUR
T1 - Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice
AU - Ageta-Ishihara, Natsumi
AU - Yamakado, Hodaka
AU - Morita, Takao
AU - Takai, Satoko
AU - Takao, Keizo
AU - Miyakawa, Tsuyoshi
AU - Takahashi, Ryosuke
AU - Kinoshita, Makoto
PY - 2013/8/13
Y1 - 2013/8/13
N2 - 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 SEPT4 54kDa 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.
AB - 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 SEPT4 54kDa 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.
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U2 - 10.1186/1756-6606-6-35
DO - 10.1186/1756-6606-6-35
M3 - Article
C2 - 23938054
AN - SCOPUS:84881167474
VL - 6
JO - Molecular Brain
JF - Molecular Brain
SN - 1756-6606
IS - 1
M1 - 35
ER -