Proteolysis has multiple functions in the nervous system, and participates in such processes as protein turnover, formation and inactivation of neuropeptides, elimination of excess or damaged cells, and activation and inactivation of enzymes. Protein catabolism is altered during growth and differentiation, and in response to physiological and pharmacological alterations. Changes were observed in a number of pathological conditions, and there are indications that proteolysis is altered in aging and that such changes may be at lest in part responsible for pathological changes in senile dementia. A further understanding of protein catabolism during aging is crucial to our understanding of the aging process, of senile changes in proteins, and would contribute to our understanding of cerebral protein turnover. The present project will measure changes during aging in cerebral protein breakdown in vivo and in vitro. In vivo protein breakdown will be measured by measuring the decay of label of prelabeled proteins in several fractions (cellular, subcellular, and membrane fractions), prepared from several brain areas in male and female rats. For in vitro experiments, cathepsin D, Ca-activated neutral proteases, and a number of brain proteins representing structural, membrane, cell-specific proteins and enzymes will be purified, and the breakdown of the substrates by the enzymes will be measured with quantitative gel electrophoresis in a crossover design (testing adult and senescent enzyme on substrate from adult and senescent brain) in several brain regions. We will also test changes in total and soluble acid and neutral protease activity. Any specific area or fraction showing changes will be investigated in greater detail.
The aim of the present phase of this study is to examine changes in vivo catabolism of selected brain protein fractions and changes in the properties of the proteases during aging. We hope to be able to identify specific proteins whose catabolism is altered and to indicate the changes involved in the properties of the substrates or enzymes. In further work we hope to study age- related changes in catabolism of other brain proteins and to study possible changes in other factors such as endogenous inhibitors, substrate phosphorylation, endocrine influences, etc.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG005607-02
Application #
3116249
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1987-01-15
Project End
1989-12-31
Budget Start
1988-01-01
Budget End
1988-12-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962
Hui, K S; Saito, M; Hui, M et al. (1993) Two cytosolic puromycin-sensitive aminopeptidase isozymes in chicken brain: molecular homology to brain-specific 14-3-3 protein. Neurochem Int 22:445-53
Kenessey, A; Banay-Schwartz, M; DeGuzman, T et al. (1990) Calpain II activity and calpastatin content in brain regions of 3- and 24-month-old rats. Neurochem Res 15:243-9