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 ?-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 ?-synuclein to create a triple transgenic line (TTG) to determine the downstream effects of elevated biogenic aldehydes on ?-synuclein. Preliminary behavioral studies show that elevated biogenic aldehydes accelerate the age-related decline in measures of gait, rotarod performance, pole-test and fine motor performance in TTG mice. Our overall aim in the next period of funding is to understand mechanistically the link between biogenic aldehydes and ?-synuclein in vivo in dopaminergic dysfunction. We will then evaluate aldehydes as therapeutic targets for FDA approved agents that reduce toxic aldehyde levels to slow or prevent the neuropathological and behavioral manifestations of PD.
The Specific Aims are:
Specific Aim 1 : To determine whether elevated biogenic aldehydes exacerbates behavioral deficits in mice overexpressing human wildtype ?Syn.
Specific Aim 2 : To determine whether elevated biogenic aldehydes exacerbate neurochemical and histopathological changes in mice overexpressing human wildtype ?Syn.
Specific Aim 3 : To determine whether hydralazine, an agent that traps aldehydes, will rescue behavioral and neurochemical changes observed in Aims 1 and 2. The work proposed will potentially identify new therapeutic targets and agents for treatment of veterans with Parkinson's disease.
The etiology of Parkinson's disease (PD) is largely unknown. Preclinical and epidemiological studies provide a strong link between old age, prior exposure to pesticides and the increased risk of developing Parkinson's disease. This is of particular relevance to the VA because military personnel are often exposed to environmental toxins, including pesticides, during deployment. Moreover, the veteran population is older than the U.S. population and thus at increased risk. Recent evidence supports a role for elevated biogenic aldehydes in PD. The work proposed will not only help to elucidate the mechanisms underlying Parkinson's disease, but it will determine whether agents that lower biogenic aldehydes may be neuroprotective in Parkinson's disease. The test agent and potential alternatives are FDA-approved drugs for which there is abundant information on their safety and efficacy. Therefore, if these preclinical studies show efficacy in models of PD, then they may be more easily tested clinically.
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