Abstract
Previous studies have reported elevated levels of biogenic aldehydes in the brains of patients with Parkinson's disease (PD). In the brain, aldehydes are primarily detoxified by aldehyde dehydrogenases (ALDH). Reduced ALDH1 expression in surviving midbrain dopamine neurons has been reported in brains of patients who died with PD. In addition, impaired complex I activity, which is well documented in PD, reduces the availability of the NAD+ co-factor required by multiple ALDH isoforms to catalyze the removal of biogenic aldehydes. We hypothesized that chronically decreased function of multiple aldehyde dehydrogenases consequent to exposure to environmental toxins and/or reduced ALDH expression, plays an important role in the pathophysiology of PD. To address this hypothesis, we generated mice null for Aldh1a1 and Aldh2, the two isoforms known to be expressed in substantia nigra dopamine neurons. Aldh1a1−/−×Aldh2−/− mice exhibited age-dependent deficits in motor performance assessed by gait analysis and by performance on an accelerating rotarod. Intraperitoneal administration of L-DOPA plus benserazide alleviated the deficits in motor performance. We observed a significant loss of neurons immunoreactive for tyrosine hydroxylase (TH) in the substantia nigra and a reduction of dopamine and metabolites in the striatum of Aldh1a1−/−×Aldh2−/− mice. We also observed significant increases in biogenic aldehydes reported to be neurotoxic, including 4-hydroxynonenal (4-HNE) and the aldehyde intermediate of dopamine metabolism, 3,4-dihydroxyphenylacetaldehyde (DOPAL). These results support the hypothesis that impaired detoxification of biogenic aldehydes may be important in the pathophysiology of PD and suggest that Aldh1a1−/−×Aldh2−/− mice may be a useful animal model of PD.
Highlights
Parkinson’s disease (PD) is the 2nd most prevalent neurodegenerative disease
There was no interaction between genotype and age on body weight (F2,176 = 1.213, p = 0.30) in Figure 1B, there was no effect of genotype on grip strength (F1,103 = 0.0357, p = 0.850) in Aldh1a12/26Aldh22/2 mice, but there was a significant effect of age on grip strength (F2,103 = 5.558, p = 0.015)
It was recently reported that patients who died with PD had an elevated DOPAL-to-dopamine ratio in caudate and putamen [11]
Summary
Parkinson’s disease (PD) is the 2nd most prevalent neurodegenerative disease. It is classically diagnosed by the presence of movement and gait abnormalities, and involves non-motor features, including autonomic and cognitive manifestations [1]. Pathological hallmarks of PD include age-progressive degeneration of mesencephalic dopamine neurons and, in surviving neurons, the presence of Lewy bodies, cytoplasmic inclusions of which asynuclein is a major constituent [2]. Numerous studies have implicated mitochondrial dysfunction and elevated oxidative stress [4]. In addition to genetic and environmental factors that can contribute to oxidative stress and mitochondrial dysfunction, excess biogenic aldehydes may play an important role [5]. Elevated levels of 4-hydroxynonenal (4-HNE), the end product of lipid peroxidation, have been reported in affected brain regions of patients dying with PD and increased ratio of 3,4dihydroxyphenlyacetaldehdye (DOPAL), the first product of dopamine metabolism by monoamine oxidase (MAO), relative to dopamine have been reported in the brains of PD patients [7,10,11]
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