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Rapamycin protects against rotenone-induced apoptosis through autophagy induction.
Neuroscience. 2009 Dec 01; 164(2):541-51.N

Abstract

Ubiquitin proteasome system (UPS) and autophagy lysosome pathway (ALP) are the two most important routes for degradation of aggregated/misfolded proteins. Additionally, ALP is so far the only known route to clear entire organelles, such as mitochondria. We proposed that enhancement of ALP may be beneficial for some neurodegenerative disorders, such as Parkinson's disease (PD), in which the accumulation of aggregated/misfolded proteins and the dysfunction of mitochondria are the two major pathogenesis. Mitochondrial complex I inhibitor rotenone, which causes dysfunction mitochondria and UPS, has been considered as one of the neurotoxins related to PD. In this study, rotenone-exposed human neuronal SH-SY5Y cells were used as an in vitro model for us to determine whether autophagy enhancer rapamycin could protect against rotenone-induced injury and its underlying mechanisms. The observed results showed that rapamycin alleviated rotenone-induced apoptosis, whose effects were partially blocked when autophagy related gene 5 (Atg5) was suppressed by Atg5 small interference RNA (siRNA) transfection. Additionally, the results showed that rapamycin pretreatment diminished rotenone-induced accumulation of high molecular weight ubiquitinated bands, and reduced rotenone-induced increase of cytochrome c in cytosolic fraction and decreased mitochondrial marker cytochrome oxidase subunit IV (COX IV) in mitochondrial fraction. The changes in cytochrome c and COX IV indicated that the decreased translocation of cytochrome c from mitochondria to cytosol was probably due to the turn over of entire injured mitochondria. The results that lysosome and mitochondria were colocolized within the cells pretreated with rapamycin and that the mitochondria could be found within autophagy double membrane structures further supported that the damaged mitochondria might be cleared through autophagy, which process has been termed as "mitophagy." Our studies suggested that autophagy enhancer rapamycin is neuroprotective against rotenone-induced apoptosis through autophagy enhancement. We concluded that pharmacologically induction of autophagy by rapamycin may represent a useful therapeutic strategy as disease-modifiers in PD.

Authors+Show Affiliations

Parkinson Disease Research Laboratory, Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19682553

Citation

Pan, T, et al. "Rapamycin Protects Against Rotenone-induced Apoptosis Through Autophagy Induction." Neuroscience, vol. 164, no. 2, 2009, pp. 541-51.
Pan T, Rawal P, Wu Y, et al. Rapamycin protects against rotenone-induced apoptosis through autophagy induction. Neuroscience. 2009;164(2):541-51.
Pan, T., Rawal, P., Wu, Y., Xie, W., Jankovic, J., & Le, W. (2009). Rapamycin protects against rotenone-induced apoptosis through autophagy induction. Neuroscience, 164(2), 541-51. https://doi.org/10.1016/j.neuroscience.2009.08.014
Pan T, et al. Rapamycin Protects Against Rotenone-induced Apoptosis Through Autophagy Induction. Neuroscience. 2009 Dec 1;164(2):541-51. PubMed PMID: 19682553.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rapamycin protects against rotenone-induced apoptosis through autophagy induction. AU - Pan,T, AU - Rawal,P, AU - Wu,Y, AU - Xie,W, AU - Jankovic,J, AU - Le,W, Y1 - 2009/08/12/ PY - 2009/04/25/received PY - 2009/07/31/revised PY - 2009/08/02/accepted PY - 2009/8/18/entrez PY - 2009/8/18/pubmed PY - 2010/2/13/medline SP - 541 EP - 51 JF - Neuroscience JO - Neuroscience VL - 164 IS - 2 N2 - Ubiquitin proteasome system (UPS) and autophagy lysosome pathway (ALP) are the two most important routes for degradation of aggregated/misfolded proteins. Additionally, ALP is so far the only known route to clear entire organelles, such as mitochondria. We proposed that enhancement of ALP may be beneficial for some neurodegenerative disorders, such as Parkinson's disease (PD), in which the accumulation of aggregated/misfolded proteins and the dysfunction of mitochondria are the two major pathogenesis. Mitochondrial complex I inhibitor rotenone, which causes dysfunction mitochondria and UPS, has been considered as one of the neurotoxins related to PD. In this study, rotenone-exposed human neuronal SH-SY5Y cells were used as an in vitro model for us to determine whether autophagy enhancer rapamycin could protect against rotenone-induced injury and its underlying mechanisms. The observed results showed that rapamycin alleviated rotenone-induced apoptosis, whose effects were partially blocked when autophagy related gene 5 (Atg5) was suppressed by Atg5 small interference RNA (siRNA) transfection. Additionally, the results showed that rapamycin pretreatment diminished rotenone-induced accumulation of high molecular weight ubiquitinated bands, and reduced rotenone-induced increase of cytochrome c in cytosolic fraction and decreased mitochondrial marker cytochrome oxidase subunit IV (COX IV) in mitochondrial fraction. The changes in cytochrome c and COX IV indicated that the decreased translocation of cytochrome c from mitochondria to cytosol was probably due to the turn over of entire injured mitochondria. The results that lysosome and mitochondria were colocolized within the cells pretreated with rapamycin and that the mitochondria could be found within autophagy double membrane structures further supported that the damaged mitochondria might be cleared through autophagy, which process has been termed as "mitophagy." Our studies suggested that autophagy enhancer rapamycin is neuroprotective against rotenone-induced apoptosis through autophagy enhancement. We concluded that pharmacologically induction of autophagy by rapamycin may represent a useful therapeutic strategy as disease-modifiers in PD. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/19682553/Rapamycin_protects_against_rotenone_induced_apoptosis_through_autophagy_induction_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(09)01294-9 DB - PRIME DP - Unbound Medicine ER -