WD5-1
The parkinsonian neurotoxin MPP+ induces nuclear accumulation of p62 and disrupts the Keap1-Nrf2 pathway
パーキンソン病関連神経毒MPP+によるp62の核内蓄積とKeap1-Nrf2経路の破綻
Watanabe Namiko（渡辺 南海子）1，宮良 政嗣1,2,3，桑原 由佳1，徳永 航1，坂本 修一朗1，石田 慶士1,2,3，太田 茂1,4，古武 弥一郎1
1Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
2Gifu Pharmaceutical University, Gifu, Japan
3Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
4Wakayama Medical University, Wakayama, Japan
Parkinson’s disease (PD) is a neurodegenerative movement disorder, but the pathogenic mechanism of PD has remains to be fully elucidated. Interestingly, recent studies have implicated a relationship between the onset of PD and autophagy dysfunction. Furthermore, we found that the neurotoxin MPP+ used for modelling PD also leads to the inhibition of autophagy. Remarkably, 200 μM MPP+ treatment of SH-SY5Y cells for 48 h induced the nuclear accumulation of p62, an autophagy selective substrate protein. Autophagy inhibition also resulted in the aggregation of p62 in the cytoplasm and not in the nucleus in other experimental paradigms. We therefore sought to investigate the factor mediating this nuclear localization and the physiological significance of this phenomenon. For better understanding of the translocation mechanism, we examined the levels of the nucleocytoplasmic transporter proteins XPO1, Ran, RanBP1, RCC1, and RanGAP1 using western blotting and measured the activity of Ran, and found that these factors were not affected by MPP+ exposure. We then focused on the effects of MPP+ on the Keap1-Nrf2 pathway, as it is well-known that p62 plays an important role in the regulation of the oxidative stress response system in the cytoplasm. We found that MPP+ treatment reduced the level of Nrf2 in the nucleus where it functions as a transcription factor in response to oxidative stress and the emergence of intracellular reactive oxygen species. In summary, we show that MPP+-induced p62 nuclear-localization is not mediated by changes in the expression of nucleocytoplasmic transporters; however, the function of p62 in the cytoplasm was indeed disrupted. Further research for understanding the cause and effect of p62 relocation would improve our understanding of PD pathogenesis. | | WD5-2
Heart-type fatty acid-binding protein accelerates α-synuclein oligomerization in dopaminergic neurons in Parkinson's disease model
心臓型脂肪酸結合タンパク質はドパミン神経におけるαシヌクレインの凝集を促進する
Matsuo Kazuya（松尾 和哉），矢吹 悌，塩田 倫史，福永 浩司
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
[Background] Long-chain polyunsaturated fatty acids such as arachidonic acid (AA) are involved in α-synuclein (α-syn) oligomerization as pathogenesis of Parkinson’s disease (PD). Fatty acid-binding protein 3 (FABP3) also named heart-type FABP is necessary for AA transport into mammalian brain. We previously demonstrated that FABP3 is abundantly expressed in dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) in mice (Shioda et al, J Biol Chem, 2014;289:18957-18965). However, it remains unclear how FABP3 mediates neurodegeneration of DA neurons in PD.
[Methods] 1-methyl-1,2,3,6-tetrahydropiridine (MPTP) was administered to wild-type (WT) and FABP3 knockout (KO) mice, and assessed behavioral and neuropathological alterations.
[Results] AA treatment induced α-syn oligomerization and cell death in FABP3-overexpresssed PC12 cells, which were significantly attenuated by overexpression of mutated FABP3 which lacks fatty acid-binding capacity. The α-syn immunoreactivity was mainly localized in the nerve terminals in the SNpc in saline-treated WT mice, whereas in DA cell bodies in the SNpc in MPTP-treated WT mice. FABP3 immunoreactivity was partly co-localized with α-syn immunoreactivity in DA neurons. Additionally, MPTP-induced DA neuronal loss and motor deficits were reduced in FABP3 null mice. Furthermore, α-syn accumulation and oligomerization in the SNpc were significantly suppressed in FABP KO mice.
[Conclusion] We here demonstrated that FABP3 is involved in α-syn oligomerization and aggregation in DA neurons with AA. We also provide evidence that FABP3 inhibitors prevent α-syn oligomerization in PD model mice. |
