Neurodegeneration and Motor Dysfunction in Mice Lacking Cytosolic and Mitochondrial Aldehyde Dehydrogenases: Implications for Parkinson's Disease

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.

Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease

“…Because benomyl and its metabolite MBT, but not carbendazim, inhibit ALDH activity at the concentrations used, ALDH inhibition likely confers benomyl's neurotoxicity. Additional support for the potential role of toxicant-induced ALDH inhibition in the pathogenesis of PD comes from a report from Wey et al that describes TH + neuronal loss, DOPAL accumulation, and motobehavioral deficits in mice lacking cytosolic and mitochondrial ALDH (Aldh1a1 −/− xAldh2 −/− ) (34). Their work demonstrated that ALDH inhibition can recapitulate some pathologic aspects of PD in an in vivo model.…”

Specification of dopaminergic subsets involves interplay of En1 and Pitx3

“…By contrast, aldehyde dehydrogenase (dys)function, including Ahd2, has mainly been related to PD (Fitzmaurice et al, 2013;Grünblatt et al, 2010), probably for its important role in DA detoxification and/or RA production from vitamin A. In addition, Ahd2/Aldh2 combined knockout mice display significant Th+ neuron loss in the SNc, reduction of dopamine and metabolites in the striatum, and agedependent deficits in motor performance, that can be alleviated by L-DOPA administration (Wey et al, 2012). Given these important physiological and functional differences between Ahd2 and Cck function in DA neurons, detailed understanding of En1 and Pitx3 in the differential coding of the Ahd2+ and Cck+ mdDA subsets is of crucial importance, and may hold translational value given the association of polymorphisms in Pitx3 and En1 with sporadic PD (Haubenberger et al, 2011).…”

Inhibition of ALDH2 expression aggravates renal injury in a rat sepsis syndrome model

“…Sepsis is associated with mitochondrial dysfunction and impaired oxygen consumption (16,17), ALDH2 is localized in the mitochondrial fraction, and mitochondrial dysfunction changes ALDH2 function. A number of studies have reported that ALDH2 protects against organ injury, such as that affecting the kidneys, heart and neurons (10,(18)(19)(20). Our previous studies showed that cardiac ALDH2 expression was decreased in rats with diabetes, or myocardial ischemia and reperfusion injury, and that upregulation of ALDH2 protected against myocardial injury and protected the lungs against diabetes-induced lung injury, all of which indicate that ALDH2 could be an intrinsic factor regulating the occurrence of disease (12,21,22).…”