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 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.

• Authors: Natsumi Ageta-Ishihara, Hodaka Yamakado, Takao Morita, Satoko Hattori, Keizo Takao, Tsuyoshi Miyakawa, Ryosuke Takahashi, Makoto Kinoshita
• Journal: Molecular brain (Mol Brain) Vol. 6 Pg. 35 (Aug 11 2013) ISSN: 1756-6606 [Electronic] England
• PMID: 23938054 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dopamine Plasma Membrane Transport Proteins
• Peptides
• alpha-Synuclein
• Methamphetamine
• Tyrosine 3-Monooxygenase
• Ubiquitin-Protein Ligases
• parkin protein
• Sept4 protein, mouse
• Septins
• Dopamine

Topics

• Animals
• Behavior, Animal (drug effects)
• Circadian Rhythm (drug effects)
• Dopamine (metabolism)
• Dopamine Plasma Membrane Transport Proteins (metabolism)
• Exploratory Behavior (drug effects)
• Humans
• Methamphetamine (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neostriatum (drug effects, enzymology, pathology)
• Nerve Degeneration (complications, metabolism, pathology)
• Parkinson Disease (complications, metabolism, pathology)
• Peptides (metabolism)
• Protein Structure, Quaternary
• Rats
• Septins (chemistry, metabolism)
• Solubility
• Substrate Specificity (drug effects)
• Tyrosine 3-Monooxygenase (metabolism)
• Ubiquitin-Protein Ligases (metabolism)
• alpha-Synuclein (metabolism)