The proteasome is an intracellular protease that is responsible for a significant amount of intracellular proteolysis. Inhibition of the proteasome-proteolytic pathway is thought to occur as a part of normal aging in most tissues. Proteasome inhibition likely contributes to numerous age-related alterations in the proteome, and thereby promotes a variety of cell disturbances during aging, although the lack of rigorous biochemical and proteomic analysis has made such estimations largely hypothetical and theoretical. Dietary restriction (DR) increases average and maximal lifespan in mammals, and suppresses a variety of deleterious age-related alterations at both the cellular and systems level. Our data suggests that DR ameliorates age-related impairments in proteasome function within the central nervous system (CNS). The focus of this proposal is to test the hypothesis that DR ameliorates age-related impairments in proteasome function in the CNS, as the result of direct effects on the proteasome complex. Additionally, we hypothesize that this preservation of proteolysis by DR contributes to maintenance of the proteome and inhibition of cellular disturbances during aging of the CNS.
The specific aims are as follows: (1) to test the hypothesis that DR alters age-related alterations in the biogenesis, composition, and oxidation of proteasome complexes in selective regions of the CNS; (2) to test the hypothesis that DR alters age-related changes in proteasome function in selective regions of the CNS; (3) to identify which proteins in the CNS exhibit decreased degradation following proteasome inhibition; (4) to test the hypothesis that DR ameliorates age-related elevations in key proteasome substrates within the CNS. Together, these data will significantly contribute to our understanding of the molecular basis for DR-induced effects in the CNS, and contribute to our understanding of how DR ameliorates age-related impairments in proteasome function in the CNS. Additionally, these data will contribute to our understanding of how proteasome inhibition promotes disruptions in the proteome, and ultimately contributes to cellular dysfunction in the CNS. Such data may not only be important to our understanding of aging in the CNS, but may identify novel therapeutic targets for aging and age-related diseases of the CNS. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
7R01AG029885-02
Application #
7564171
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Wise, Bradley C
Project Start
2007-09-01
Project End
2012-08-31
Budget Start
2008-03-15
Budget End
2008-08-31
Support Year
2
Fiscal Year
2007
Total Cost
$271,274
Indirect Cost
Name
Lsu Pennington Biomedical Research Center
Department
Type
DUNS #
611012324
City
Baton Rouge
State
LA
Country
United States
Zip Code
70808
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Beckett, Tina L; Webb, Robin L; Niedowicz, Dana M et al. (2012) Postmortem Pittsburgh Compound B (PiB) binding increases with Alzheimer's disease progression. J Alzheimers Dis 32:127-38
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Dasuri, Kalavathi; Ebenezer, Philip J; Uranga, Romina M et al. (2011) Amino acid analog toxicity in primary rat neuronal and astrocyte cultures: implications for protein misfolding and TDP-43 regulation. J Neurosci Res 89:1471-7
Dasuri, Kalavathi; Ebenezer, Philip J; Zhang, Le et al. (2010) Selective vulnerability of neurons to acute toxicity after proteasome inhibitor treatment: implications for oxidative stress and insolubility of newly synthesized proteins. Free Radic Biol Med 49:1290-7
Dasuri, Kalavathi; Ebenezer, Philip; Zhang, Le et al. (2010) Increased protein hydrophobicity in response to aging and Alzheimer disease. Free Radic Biol Med 48:1330-7
Zhang, Le; Ebenezer, Philip J; Dasuri, Kalavathi et al. (2010) Activation of PERK kinase in neural cells by proteasome inhibitor treatment. J Neurochem 112:238-45
Uranga, Romina M; Bruce-Keller, Annadora J; Morrison, Christopher D et al. (2010) Intersection between metabolic dysfunction, high fat diet consumption, and brain aging. J Neurochem 114:344-61
Zhang, Le; Ebenezer, Philip J; Dasuri, Kalavathi et al. (2009) Proteasome inhibition modulates kinase activation in neural cells: relevance to ubiquitination, ribosomes, and survival. J Neurosci Res 87:3231-8

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