Detoxification of Biogenic Aldehydes in Parkinson¡¦s Disease

Abstract

It has been recognized for almost 20 years that idiopathic Parkinson's disease (PD) is linked to diminished NADH dehydrogenase (mitochondrial complex I) activity. How chronic complex I inhibition leads to the characteristic pathological features of PD is largely unknown. PD is accompanied by elevation of neurotoxic biogenic aldehydes, including 4‐hydroxynonenal, a product of lipid peroxidation, and 3, 4‐dyhydroxyphenylacetaldehyde, a product of dopamine metabolism. We hypothesize that impaired complex 1 activity reduces the availability of the NAD+ co‐factor required by ALDHs to detoxify aldehydes. Aldh1a1 and Aldh2, are the only ALDH genes known to be expressed in midbrain brain dopamine neurons. Moreover, expression of ALDH1, the human homologue of Aldh1a1, is reduced in PD. Therefore, we tested the hypothesis that mice lacking both Aldh1a1 and Aldh2 would exhibit impaired motor function consequent to dopaminergic neurodegeneration. Compared to wild‐type controls, knockout mice exhibited significant age‐related decreases in the latency to fall during accelerated rotarod testing (no significant decrease at 7 months, 32% at 10 months, and 69% at 22 months). No age‐related deficits were observed in wild type controls. We will discuss neurochemical analyses of the nigrostriatal pathway in the double‐knockout mice.Supported by the VA Office of Research & Development (EF and RS) and PHS: AG022307 (RS).