抄録
Septins are ubiquitous GTP-binding proteins which form filamentous heteropolymer complexes. Although they are required for cortical organization in cell division and cellular morphogenesis, postmitotic roles of septins beneath neuronal and glial membrane are unknown. To explore their physiological functions, we examined mice lacking a brain-specific septin subunit, Sept4. By comprehensive behavioral screening, we pinpointed a hypo-dopaminergic defect in the nigrostriatal transmission. Although the nigral dopamine neurons without Sept4 were morphologically normal, the dopamine transporter (DAT) and a few related molecules were reduced from their axons projecting to the striatum. These molecules and Sept4 were colocalized in dopaminergic presynaptic terminals and co-immunoprecipitated from the striatal homogenate. Transgenic mice overexpressing Sept4 exhibited a slightly higher DAT level, and transgenic supplementation of Sept4 normalized the DAT level in Sept4−/− striatum. These data concordantly demonstrate that association of Sept4 has a positive effect on the DAT level. We hypothesize that the presynaptic septin scaffolds help organize and/or stabilize the macromolecular complex containing DAT. We previously reported that Sept4 is sequestered into α-synuclein aggregates under pathological conditions such as Parkinson disease. Thus, Sept4 insufficiency may contribute to the pathophysiology by attenuating dopaminergic neurotransmission. [J Physiol Sci. 2007;57 Suppl:S42]
