TY - JOUR
T1 - Mutation of hop-1 and pink-1 attenuates vulnerability of neurotoxicity in C. elegans
T2 - the role of mitochondria-associated membrane proteins in Parkinsonism
AU - Wu, Siyu
AU - Lei, Lili
AU - Song, Yang
AU - Liu, Mengting
AU - Lu, Shibo
AU - Lou, Dan
AU - Shi, Yonghong
AU - Wang, Zhibin
AU - He, Defu
N1 - Publisher Copyright:
© 2018
PY - 2018/11
Y1 - 2018/11
N2 - 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 μM 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 tomm-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.
AB - 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 μM 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 tomm-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.
KW - Caenorhabditis elegans
KW - Mitochondria-associated membranes
KW - Mitochondrial toxicity
KW - Parkinson's disease
KW - hop-1
KW - pink-1
UR - http://www.scopus.com/inward/record.url?scp=85050879480&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85050879480&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2018.07.018
DO - 10.1016/j.expneurol.2018.07.018
M3 - Article
C2 - 30076829
AN - SCOPUS:85050879480
SN - 0014-4886
VL - 309
SP - 67
EP - 78
JO - Experimental Neurology
JF - Experimental Neurology
ER -