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 Takai, Keizo Takao, Tsuyoshi Miyakawa, Ryosuke Takahashi, Makoto Kinoshita

Research output: Contribution to journalArticle

11 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 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 languageEnglish
Article number35
JournalMolecular Brain
Volume6
Issue number1
DOIs
Publication statusPublished - 13-08-2013

Fingerprint

Septins
Dopaminergic Neurons
Synucleins
Parkinson Disease
Brain
Dopamine Plasma Membrane Transport Proteins
Social Behavior
Prions
Parkinsonian Disorders
Ligases
Ubiquitin
Bipolar Disorder
Transgenic Mice
Virulence
Mammals
Schizophrenia
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Ageta-Ishihara, Natsumi ; Yamakado, Hodaka ; Morita, Takao ; Takai, Satoko ; Takao, Keizo ; Miyakawa, Tsuyoshi ; Takahashi, Ryosuke ; Kinoshita, Makoto. / Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice. In: Molecular Brain. 2013 ; Vol. 6, No. 1.
@article{4f0d7b276d5d4b908b88960f2ea8064e,
title = "Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice",
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.",
author = "Natsumi Ageta-Ishihara and Hodaka Yamakado and Takao Morita and Satoko Takai and Keizo Takao and Tsuyoshi Miyakawa and Ryosuke Takahashi and Makoto Kinoshita",
year = "2013",
month = "8",
day = "13",
doi = "10.1186/1756-6606-6-35",
language = "English",
volume = "6",
journal = "Molecular Brain",
issn = "1756-6606",
publisher = "BioMed Central",
number = "1",

}

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 journalArticle

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.

UR - http://www.scopus.com/inward/record.url?scp=84881167474&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84881167474&partnerID=8YFLogxK

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 -