# DETERMINANTS OF LONGEVITY IN NEURONAL CELLS

> **NIH NIH R01** · OREGON STATE UNIVERSITY · 1993 · $63,474

## Abstract

The prolonged lifespan of neurons allows them to participate in the vast
information networks underlying all nervous abilities.  To ensure
longevity and maintain integrity neurons are certain to be endowed with
elaborate housekeeping systems, but these maintenance and repair
functions are only poorly understood.  We wish to understand one of the
major maintenance tasks in the nervous system:  the prevention of the
buildup of spontaneously damaged protein.  Without preventive measures
such a buildup would be inevitable given the chemical susceptibility of
proteins to damage under the temperature and chemical conditions of
neuronal tissue.  This problem is complex and intellectually rich because
the neuron evidently can repair or destroy its damaged proteins without
disrupting the integrity of its many molecular assemblies.  This problem
is also highly relevant to human health because symptoms of impaired and
aberrant protein degradation are present in neurological disease,
specifically Alzheimer's dementia.  Our proposal is to determine the
molecular events that govern the fate of neuronal protein molecules.
These molecular events will be established in neuronally differentiated
cells of the well-described PC12 line, allowing questions on protein fate
to be addressed in large populations of clonal and therefore
biochemically identical neuronal cells.  First, we will determine the
lifespan of cell proteins to determine which proteins are turned over
rapidly, and at the other extreme which proteins persist for the lifetime
of the cell.  We will also test whether periods of intense neurosecretory
activity alter the lifespan of proteins involved in secretion since
active use of a protein may accelerate its damage.  Second, we will
identify the proteins in neuronally differentiated PC12 cells that are
methylated by an enzyme, protein D-aspartyl/L-isoaspartyl
methyltransferase (PDM), the only neuronal enzyme known to exclusively
modify damaged proteins.  Identification of these methylated proteins
will show which types of damaged proteins have their fate affected by the
methylation pathway and will indicate which functional systems in neurons
are especially dependent on methylation for repair or degradation of
damaged proteins.  Third, we will measure the dynamics of protein
methylation and demethylation to establish the number of times that a
protein is methylated during its lifetime.  The effect of neurosecretion
on methylation and demethylation will also be measured to test whether
intense secretory activity may be a stress that is followed by a period
of repair and degradation initiated by protein methylation.  Fourth, we
will test the fate of damaged neuronal proteins in cells which are
impaired in methylation activity since it can be predicted that blocking
the PDM activity of neuronal cells will lead to hyperaccumulation of
damaged protein.

## Key facts

- **NIH application ID:** 3123076
- **Project number:** 1R01AG011087-01
- **Recipient organization:** OREGON STATE UNIVERSITY
- **SAM.gov UEI:** MZ4DYXE1SL98
- **Principal Investigator:** PHILIP N MCFADDEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $63,474
- **Award type:** 1
- **Project period:** 1993-01-01 → 1995-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3123076

## Citation

> US National Institutes of Health, RePORTER application 3123076, DETERMINANTS OF LONGEVITY IN NEURONAL CELLS (1R01AG011087-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3123076. Licensed CC0.

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