Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice.
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 α-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 α-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.
Department of Molecular Biology, Division of Biological Sciences, Nagoya University Graduate School of Science, Nagoya, Japan.
Natsumi
N
Ageta-Ishihara
Hodaka
H
Yamakado
Takao
T
Morita
Satoko
S
Hattori
Keizo
K
Takao
Tsuyoshi
T
Miyakawa
Ryosuke
R
Takahashi
Makoto
M
Kinoshita
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002940:Circadian Rhythm / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects; D006801:Humans; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009410:Nerve Degeneration / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D010300:Parkinson Disease / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D010455:Peptides / Q000378:metabolism; D020836:Protein Structure, Quaternary; D051381:Rats; D058112:Septins / Q000737:chemistry* / Q000378:metabolism*; D012995:Solubility; D013379:Substrate Specificity / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D010455:Peptides; D051844:alpha-Synuclein; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C115474:Sept4 protein, mouse; D058112:Septins; D004298:Dopamine