Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement.
The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP) are the two most important cellular mechanisms for protein degradation. To investigate the role of autophagy in reversing neuronal injury, the proteasome inhibitor lactacystin was used to cause UPS dysfunction in differentiated PC12 cells and in C57BL/6 mice and rapamycin was used as an autophagy enhancer. The results showed that rapamycin pre-treatment attenuated lactacystin-induced apoptosis and reduced lactacystin-induced ubiquitinated protein aggregation in differentiated PC12 cells. The observed protection was partially blocked by the autophagy inhibitor 3-methyladenine. Furthermore, post-treatment of mice with rapamycin significantly attenuated lactacystin-induced loss of nigral DA neurons and the reduction of striatal DA levels. The lactacystin-induced high molecular ubiquitinated proteins were also attenuated by rapamycin treatment in vivo. In addition, as a chemical compound, rapamycin caused an increase of bcl2 protein level and blocked the release of cytochrome c from mitochondria to cytosal. We concluded that the neuroprotective effect of rapamycin is partially mediated by autophagy enhancement through enhanced degradation of misfolded proteins and autophagy enhancement may be considered to be a promising strategy to prevent diseases associated with misfolded/aggregated proteins, such as Parkinson's disease.
Pan
Tianhong
T
Parkinson Disease Research Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
Kondo
Seiji
S
Zhu
Wen
W
Xie
Wenjie
W
Jankovic
Joseph
J
Le
Weidong
W
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016716:PC12 Cells; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D017510:Protein Folding / Q000187:drug effects; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*
D018696:Neuroprotective Agents; C067713:lactacystin; D020123:Sirolimus; D000111:Acetylcysteine