# Detoxification of Biogenic Aldehydes in Parkinson's Disease

> **NIH VA I01** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2020 · —

## Abstract

Parkinson's disease (PD) is the second most prevalent age-related neurodegenerative disorder, after
Alzheimer's disease, affecting up to 5% of the population aged 65 – 85 years. Veterans are at increased risk for
PD because the veteran population is older than the United States population as a whole and because veterans
are more likely to have been exposed to toxic environmental agents during deployment. Despite great strides in
research over the past two decades, the etiology and pathogenesis of the disease is still largely unknown.
Although families have been identified with single gene mutations, the majority of PD cases are classified as
idiopathic. Animal studies, and subsequent epidemiological studies, have established a link between
environmental exposure to agents such as paraquat, maneb and rotenone in idiopathic or sporadic PD. The
mechanisms by which exposure to pesticides with different mechanisms of action may increase the risk of PD
are not fully understood, and treatment strategies to prevent or slow disease progression have not been
identified. However, a growing body of evidence from our lab and others has implicated impaired aldehyde
detoxification. For example, cytosolic aldehyde dehydrogenase (ALDH1) expression is reduced in the SN of PD
patients. The widespread reduction in ALDH1 in central and peripheral tissues in sporadic PD has suggested
the possibility of using it as a diagnostic biomarker. Epidemiological studies of the farming communities in the
Central Valley in California have linked polymorphisms in mitochondrial aldehyde dehydrogenase (ALDH2) to
enhanced risk of PD in people exposed to agricultural pesticides.
 Our working hypothesis is that impaired aldehyde detoxification consequent to exposure to
environmental agents, and/or reduced aldehyde dehydrogenase expression leads to elevated “aldehyde
load” including increased levels of 3,4-dihydroxyphenylacetaldehyde (DOPAL) and 4-hydroxynonenal
(4-HNE), aldehyde products of dopamine metabolism and lipid peroxidation, respectively. We
hypothesize that these aldehydes may form adducts with α-synuclein producing toxic fibrils that cause
neurodegeneration. To test this hypothesis in vivo, we created a line of mice with homozygous mutations in
the only two aldehyde dehydrogenase isozymes, Aldh1a1 and Aldh2, known to be present in midbrain dopamine
neurons. The Aldh1a1-/-xAldh2-/- (DKO) mice exhibit elevation of DOPAL and 4-HNE that precedes age-related
impairments in motor function, reduced dopamine and metabolites, and loss of midbrain dopamine neurons
starting around 12 months of age and continuing to progress to at least 23 months of age. We then crossed this
line of mice to mice overexpressing human wild-type α-synuclein to create a triple transgenic line (TTG) to
determine the downstream effects of elevated biogenic aldehydes on α-synuclein. Preliminary behavioral studies
show that elevated biogenic aldehydes accelerate the age-related decline in measures of gait, rot...

## Key facts

- **NIH application ID:** 9783957
- **Project number:** 2I01BX001641-05A1
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** RANDY STRONG
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2013-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9783957

## Citation

> US National Institutes of Health, RePORTER application 9783957, Detoxification of Biogenic Aldehydes in Parkinson's Disease (2I01BX001641-05A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9783957. Licensed CC0.

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