# BIOPTERIN/CATECHOLAMINE METABOLISM IN ALZHEIMER'S/AGING

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 1991 · $98,320

## Abstract

Tetrahydrobiopterin (BH4) is the cofactor for tyrosine hydroxylase and
tryptophan hydroxylase, which are the initial and rate-limiting enzymes in
catecholamine and serotonin synthesis.  BH4 is an important regulator of
catecholamine synthesis, since BH4 administration increases brain dopamine
synthesis, whereas inhibition of endogenous BH4 synthesis in brain leads to
catecholamine deficits.  Of all the genes encoding proteins involved in
pre- and postsynaptic catecholamine metabolism, only the altered expression
of genes encoding BH4 biosynthetic enzymes is known to cause human illness.
Specifically, genetic defects in the expression of any one of several BH4
biosynthetic enzymes cause BH4 deficiency in liver and brain at birth in
atypical phenylketonuria (PKU); the BH4 deficit causes brain biogenic amine
deficiency and neurological impairment.  Since many other systems requiring
biogenic amine synthesis function normally in these patients, atypical PKU
may be caused by tissue-specific regulatory mutations of BH4 metabolism.
Thus, altered expression of the "candidate genes" encoding BH4 biosynthetic
enzymes and tyrosine hydroxylase may be responsible for the BH4 and
catecholamine deficits observed in aging, Alzheimer's disease, and other
neuropsychiatric disorders, which warrants the study of BH4-related genes.
The BH4 biosynthetic enzymes to be studied are GTP cyclohydrolase and
sepiapterin reductase, which are the initial and final enzymes.  In
rodents, GTP cyclohydrolase may be the main rate-controlling enzyme in BH4
synthesis.  In humans, sepiapterin reductase may also contribute to
regulating BH4 production, though further study is required.  The first
goal of this proposal is to clone the human cDNAs for GTP cyclohydrolase
and sepiapterin reductase to examine altered genetic expression of these
enzymes and tyrosine hydroxylase in human brain in aging and Alzheimer's
disease.  Expression of these enzyme will be examined more completely by
measuring multiple parameters including tissue mRNAs, amounts of enzymes,
enzyme activities, and end-products of biosynthesis (BH4 and
catecholamines).  Part of the second goal using young and old rats is to
test the combined effects of aging and neuro-degeneration on tyrosine
hydroxylase, GTP cyclohydrolase, and sepiapterin reductase gene expression
in surviving nigrostriatal dopamine neurons following striatal kainic acid
lesions of non-dopamine neurons.  Other rats will be treated with drugs
affecting BH4 and catecholamine metabolism to investigate regulatory
interactions between BH4 and catecholamine biosynthesis.  The hypothesis
will be tested in brain and adrenal catecholamine-producing cells that
coordinate regulation causes a concomitant enhancement of GTP
cyclohydrolase and sepiapterin reductase gene expression when tyrosine
hydroxylase expression is enhanced.  Coordinate regulation will be studied
in rat brain and adrenal after treatments with: 1) inhibitors of GTP
cyclohydrolase; 2) activators of...

## Key facts

- **NIH application ID:** 3122645
- **Project number:** 1R01AG010687-01
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **SAM.gov UEI:** M6K6NTJ2MNE5
- **Principal Investigator:** ROBERT A LEVINE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1991
- **Award amount:** $98,320
- **Award type:** 1
- **Project period:** 1991-09-29 → 1994-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3122645

## Citation

> US National Institutes of Health, RePORTER application 3122645, BIOPTERIN/CATECHOLAMINE METABOLISM IN ALZHEIMER'S/AGING (1R01AG010687-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3122645. Licensed CC0.

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