Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease
Article first published online: 22 JUL 2013
Published 2013. This article is a U.S. Government work and is in the public domain in the USA.
Journal of Neurochemistry
Volume 126, Issue 5, pages 591–603, September 2013
How to Cite
J. Neurochem. (2013) 126, 591–603.
- Issue published online: 23 AUG 2013
- Article first published online: 22 JUL 2013
- Accepted manuscript online: 21 JUN 2013 03:49AM EST
- Manuscript Accepted: 17 JUN 2013
- Manuscript Revised: 13 JUN 2013
- Manuscript Received: 12 JUN 2013
- National Institute of Neurological Disorders and Stroke
- DOPAC ;
- DOPAL ;
- DOPET ;
- monoamine oxidase;
- Parkinson's disease
Intra-neuronal metabolism of dopamine (DA) begins with production of 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is toxic. According to the ‘catecholaldehyde hypothesis,’ DOPAL destroys nigrostriatal DA terminals and contributes to the profound putamen DA deficiency that characterizes Parkinson's disease (PD). We tested the feasibility of using post-mortem patterns of putamen tissue catechols to examine contributions of altered activities of the type 2 vesicular monoamine transporter (VMAT2) and aldehyde dehydrogenase (ALDH) to the increased DOPAL levels found in PD. Theoretically, the DA : DOPA concentration ratio indicates vesicular uptake, and the 3,4-dihydroxyphenylacetic acid : DOPAL ratio indicates ALDH activity. We validated these indices in transgenic mice with very low vesicular uptake (VMAT2-Lo) or with knockouts of the genes encoding ALDH1A1 and ALDH2 (ALDH1A1,2 KO), applied these indices in PD putamen, and estimated the percent decreases in vesicular uptake and ALDH activity in PD. VMAT2-Lo mice had markedly decreased DA:DOPA (50 vs. 1377, p < 0.0001), and ALDH1A1,2 KO mice had decreased 3,4-dihydroxyphenylacetic acid:DOPAL (1.0 vs. 11.2, p < 0.0001). In PD putamen, vesicular uptake was estimated to be decreased by 89% and ALDH activity by 70%. Elevated DOPAL levels in PD putamen reflect a combination of decreased vesicular uptake of cytosolic DA and decreased DOPAL detoxification by ALDH.
According to the ‘catecholaldehyde hypothesis,’ the toxic dopamine metabolite DOPAL contributes to loss of striatal dopaminergic innervation in Parkinson's disease. Here we provide post-mortem neurochemical evidence that in Parkinson's disease patients, putamen DOPAL buildup reflects decreased vesicular sequestration of cytosolic dopamine and decreased DOPAL metabolism by aldehyde dehydrogenase. The results fit with an intra-neuronal autotoxic mechanism of Parkinson's disease.