Proteasome Inhibition in Brain Aging

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The proteasome is found in all cells of the brain, and mediates the majority of overall protein degradation. In particular, the proteasome is responsible for mediating the degradation of most oxidized and damaged proteins in the brain. The proteasome is composed of multiple subunits, and degrades proteins through the coordinated efforts of at least 3 distinct proteolytic activities. Recently we have identified that there is a brain region specific impairment in the chymotrypsin-like activity of the proteasome, during normal brain aging. Recent studies from our laboratory indicate a possible role for decreased expression of heat shock proteins (HSP), and decreased expression of proteasome subunits, as a possible mechanism by which age-related proteasome inhibition occurs. Data in this proposal clearly demonstrate that inhibition of proteasome activity is sufficient to induce the accumulation of oxidized DNA in the brain, although the possible role of proteasome inhibition in mediating age-related increases in oxidative stress in the brain has not been determined previously. The focus of this proposal is to test the hypothesis that decreased expression of HSP, HSP associated proteins, and individual proteasome subunits in the brain directly contribute to age-related impairment of proteasome activity, which directly contributes to age-related increases in protein oxidation and DNA oxidation. The specific aims for testing this hypothesis are as follows: 1) To determine alterations in proteasome expression in the aging brain 2) To determine alterations in all proteasome proteolytic activities in the aging brain 3) To determine alterations in the expression of HSP, and HSP associated proteins, in the aging brain 4) To determine the mechanism by which proteasome activity is inhibited in the aging brain 5) To elucidate the role of proteasome inhibition in age-related increases in protein oxidation and DNA oxidation. Together, these studies will provide a basis for understanding proteasome biology in the brain, and elucidate the involvement of proteasome inhibition as a contributor to the deleterious effects associated with brain aging.