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 the clinical manifestations of PD include slowness of voluntary movement, resting tremor, muscle rigidity and postural instability. The major biochemical abnormality is a profound loss of dopamine in the substantia nigra (SN) and striatum, resulting from loss of dopaminergic neurons in the substantia nigra and their axon terminals in the striatum. Other prominent pathological features include the presence of intraneuronal inclusions consisting of protein aggregates containing a-synuclein and ubiquitin. 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 that cause PD-like symptoms, they account for a relatively small number of PD cases. The majority of PD cases are classified as idiopathic or of unknown cause. Human and animal studies have established a link between environmental exposure to paraquat, maneb and rotenone in idiopathic or sporadic PD. The mechanisms by which exposure to pesticides with different mechanisms of action may cause 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. Our working hypothesis is that impaired aldehyde detoxification leads to elevated "aldehyde load" including increased levels of DOPAL and 4-HNE. These aldehydes or their metabolites can form adducts with a-synuclein, leading to formation of toxic fibrils and eventually cell death. To test the hypothesis that impaired aldehyde detoxification is mechanistically linked to dopaminergic dysfunction;we created two lines of mice, one with homozygous mutations in the two aldehyde dehydrogenase isozymes, Aldh1a1 and Aldh2, that are known to be present in midbrain dopamine neurons, and the other a line of wild- type mice from their littermates on the identical genetic background. We then examined the effects of Aldh1a1/Aldh2-deficiency on their behavioral and neurochemical phenotypes. Our results show that mice deficient in Aldh1a1/Aldh2 exhibit impairments in motor function that are reversed by L-DOPA, reduced dopamine and metabolites and loss of midbrain dopamine neurons. The overall aim is to test mechanistically determine how increased aldehyde load is connected to dopaminergic dysfunction and evaluate aldehydes as a therapeutic target.
Our Specific Aims are:
Aim 1 : To determine whether impaired aldehyde detoxification increases the sensitivity of dopamine neurons to environmental neurotoxins and biogenic aldehydes;
Aim 2 To determine the role of a-synuclein in the neuropathology and behavioral deficits in Aldh1a1/Aldh2 null mice;
Aim 3 To determine the efficacy of accelerated aldehyde removal by aldehyde trapping agents on neuroprotection of midbrain dopamine neurons. The results of these studies may identify new therapeutic strategies for the treatment of 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 aldehyde trapping agents such as hydralazine may be neuroprotective in Parkinson's disease. Hydralazine is an FDA-approved drug for which there is abundant information on its safety and efficacy. Therefore, if these preclinical studies show efficacy in models of PD, then they may be more easily tested clinically.