Possible involvement of proteasome inhibition in aging: implications for oxidative stress.
Oxidative stress may contribute to the cellular alterations, which occur as the result of aging, and the nervous system is particularly vulnerable to aging associated oxidative injury. The multicatalytic proteasome (MCP) is responsible for the majority of protein degradation and is sensitive to oxidative stress. To determine if MCP activity is altered during aging, studies were conducted in multiple tissues from aged Fisher 344 rats. Analysis of heart, lung, kidney, and liver revealed decreased MCP activity in 12, 24, and 28 month old rats, compared with 3 week or 3 month old animals. The spinal cord, hippocampus, and cerebral cortex demonstrated age dependent decreases in MCP activity, but at no timepoint was MCP activity decreased in either the brain stem or cerebellum. Oxidative injury and the lipid oxidation product 4-hydroxynonenal caused decreased MCP activity in neural PC6 cells, while application of MCP inhibitors was sufficient to induce cell death in neural PC6 cells. Together, these data indicate a role for MCP inhibition in cellular dysfunction associated with aging and oxidative injury.
Keller
J N
JN
Sanders-Brown Center on Aging, University of Kentucky, Lexington 40536-0230, USA.
Hanni
K B
KB
Markesbery
W R
WR
D000375:Aging / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D002490:Central Nervous System / Q000201:enzymology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015227:Lipid Peroxidation; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D000975:Antioxidants; D009097:Multienzyme Complexes; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex