Mutation of hop-1 and pink-1 attenuates vulnerability of neurotoxicity in C. elegans: the role of mitochondria-associated membrane proteins in Parkinsonism

作者：Wu, Siyu; Lei, Lili; Song, Yang; Liu, Mengting; Lu, Shibo; Lou, Dan; Shi, Yonghong; Wang, Zhibin^*; He, Defu^*

来源：Experimental Neurology, 2018, 309: 67-78.

DOI：10.1016/j.expneurol.2018.07.018

• Parkinson's disease
• Mitochondrial toxicity
• Mitochondria-associated membranes
• hop-1
• pink-1
• Caenorhabditis elegans

Mitochondrial dysfunction is considered as a critical mechanism in the pathogenesis of Parkinson's disease (PD). Increasing evidence supports the notion of mitochondria-associated membranes (MAMs) in mitochondrial dysfunction; yet little is known about the role of MAMs-related proteins in the pathogenesis of PD. Herein we exposed the nematode Caenorhabditis elegans to 0.5-10.0 mu M rotenone (RO) or 0.2-1.6 mM paraquat (PQ) for 3 days. Our results showed that both RO and PQ induced similar Parkinsonism including motor deficits and dopaminergic degeneration. RO/PQ caused mitochondrial damages characterized by the increase of vacuole areas and autophagy vesicles, but the decrease of mitochondrial cristae. RO/PQ-impacted mitochondrial function was also demonstrated by the decrease of ATP level and mitochondrial membrane potential. Additionally, the attachment or surrounding of endoplasmic reticulum to the damaged mitochondria indicates ultrastructural alterations in MAMs. Using fluorescently labeled transgenic nematodes, we further found that the expression of torrun-7 and genes of Complex I, II and III was reduced, whereas the expression of pink-1 was increased in the exposed animals. To determine MAMs in toxicity toward PD, we investigated the mutants of hop-1 and pink-1, encoding presenilin and PTEN-induced putative kinase 1 (PINK1) in mitochondria-associated membranes, respectively. Results demonstrated that the mutation of both hop-1 and pink-1 reduced the vulnerability of lethal, behavioral, and mitochondrial toxicity induced by RO/PQ. These findings suggest that presenilin and PINK1 play important roles in the RO/PQ-induced neurotoxicity through the mechanisms involved in mitochondria-associated membranes.

• 出版日期2018-11
• 单位华东师范大学; 中国农业科学院; 中国农业科学院上海兽医研究所