Drp1, a potential therapeutic target for Parkinson's disease, is involved in olfactory bulb pathological alteration in the Rotenone-induced rat model. (1st June 2020)

• Record Type: Journal Article
• Authors: Zhang, Xiaoling; Huang, Wenmin; Shao, Qianhang; Yang, Yuan; Xu, Zhengxin; Chen, Jing; Zhang, Xiaoyan; Ge, Xiaoqun
• Is Part Of: Toxicology letters. Volume 325(2020)
• Page Start: 1
• Page End: 13
• Publication Date: 2020-06-01
• Subjects: PD Parkinson's disease -- TH tyrosine hydroxylase -- Mdivi-1 mitochondrial fission inhibitor -- GI gastrointestinal -- α-syn α-synuclein -- CNS central nervous system -- NLRP3 leucine-rich repeat and pyrin domain-containing (NLRP) 3 -- SN substantia nigra -- Drp1 dynamin-related protein 1 -- Fis1 fission protein 1 -- NF-κB nuclear factor-kappa B -- mROS mitochondrial reactive oxygen species -- mtDNA mitochondrial DNA -- DMSO dimethyl sulfoxide -- PEG polyethylene glycol -- DA dopamine -- IL-1β interleukin-1β -- IL-18 interleukin-18 -- SNpc substantia nigra pars compacta -- iNOS cytokine-inducible NOS; Parkinson's disease -- Olfactory bulb -- Mitochondrial fission -- Drp1 -- NLRP3 inflammasome -- Rotenone; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2020.02.009
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Highlights: Rotenone induces the DA degenration in the olfactory bulb. Drp1 mitochondrial recruitment leads to excessive mitochondrial fission and abnormal morphology. Drp1-mediated mitochondrial fission activates the NLRP3 inflammasome of the olfactory bulb. The pathological alteration of olfactory bulb is closely associated with Drp1-dependent mitochondrial fragmentation. Abstract: Olfaction is often affected in parkinsonian patients and its disturbances precede the classical cognitive and locomotor dysfunction. The olfactory bulb might be the region of onset in Parkinson's disease (PD) pathogenesis, evidenced by the presence of disease-related protein aggregates and disturbed olfactory information processing. However, the underlying molecular mechanism that governs the olfactory bulb impairments remains unclear. This study was designed to investigate the relationship between olfactory bulb and inflammatory pathological alterations and the potential mechanisms. Here we found that rotenone led to typical parkinsonian symptoms and decreased tyrosine hydroxylase (TH)-positive neurons in the olfactory bulb. Additionally, increased NF-κB nuclear translocation and NLRP3 inflammasome components expressions caused by rotenone injection were observed accompanied by the activation of microglia and astrocytes in the olfactory bulb. Rotenone also triggered Drp1-mediated mitochondrial fission and this in turn caused mitochondrial damage. Furthermore, Mdivi-1(a selective Drp1 inhibitor) markedly ameliorated the morphologic disruptions of mitochondria and Drp1 translocation, inhibited the nuclear translocation of NF-κB, eventually blocked the downstream pathway of the NLRP3/caspase-1/IL-1β axis and expression of iNOS. Overall, these findings suggest that Drp1-dependent mitochondrial fission induces NF-κB nuclear translocation and NLRP3 inflammasome activation that may further contribute to olfactory bulb disturbances.