Abstract
BackgroundIn 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 SEPT454kDa via the prion promoter in the entire brain.ResultsHistological 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 Sept4Tg/+ 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 Sept4Tg/+ mice that include consistent attenuation of voluntary activities in distinct behavioral paradigms and altered social behaviors.ConclusionsTogether, 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.
Highlights
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
The potential toxicity of septin overload is suggested by the following biochemical evidence and findings from animal models: Two paralogous septin subunits, SEPT5/CDCrel-1 [3] and SEPT4/ CDCrel-2 are the substrates of ubiquitination by parkin, an E3 ubiquitin protein ligase whose loss of function is responsible for autosomal recessive early-onset parkinsonism (ARJP/PARK2) and a subset of sporadic PD
We examined the spatial expression pattern of the transgene-derived SEPT454kDa in parasagittal and coronal brain sections by immunofluorescence with an antibody H5C2U that recognizes a carboxyl-terminal sequence shared by the major Sept4-derived polypeptides including SEPT454kDa
Summary
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. The potential toxicity of septin overload is suggested by the following biochemical evidence and findings from animal models: Two paralogous septin subunits, SEPT5/CDCrel-1 [3] and SEPT4/ CDCrel-2 (misnamed as SEPT5_v2 in [4]) are the substrates of ubiquitination by parkin, an E3 ubiquitin protein ligase whose loss of function is responsible for autosomal recessive early-onset parkinsonism (ARJP/PARK2) and a subset of sporadic PD. The first step in this scenario is supported by the accumulation of SEPT5/7/8/11 in the striata of parkin-null mice [5] and of SEPT5 in dopamine neurons of transgenic mice that express a dominant negative mutant of parkin [6]. The presumed neurotoxicity by an excess of SEPT5 and other septins awaits further assessments with rigorous quantification of the expression level
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