Work

Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease

Year: 2013

Type: article

Abstract: Intra‐neuronal metabolism of dopamine (DA) begins with production of 3,4‐dihydroxyphenylacetaldehyde (DOPAL), which is toxic. According to the ‘catecholaldehyde hypothesis,’DOPALdestroys nigrostriatalDAterminals and contributes to the profound putamenDAdeficiency 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 increasedDOPALlevels found inPD. Theoretically, theDA : DOPAconcentration ratio indicates vesicular uptake, and the 3,4‐dihydroxyphenylacetic acid : DOPALratio indicatesALDHactivity. We validated these indices in transgenic mice with very low vesicular uptake (VMAT2‐Lo) or with knockouts of the genes encodingALDH1A1 andALDH2 (ALDH1A1,2KO), applied these indices inPDputamen, and estimated the percent decreases in vesicular uptake andALDHactivity inPD.VMAT2‐Lo mice had markedly decreasedDA:DOPA(50 vs. 1377,p < 0.0001), andALDH1A1,2KOmice had decreased 3,4‐dihydroxyphenylacetic acid:DOPAL(1.0 vs. 11.2,p < 0.0001). InPDputamen, vesicular uptake was estimated to be decreased by 89% andALDHactivity by 70%. ElevatedDOPALlevels inPDputamen reflect a combination of decreased vesicular uptake of cytosolicDAand decreasedDOPALdetoxification byALDH. image 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.

Source: Journal of Neurochemistry

DOI: 10.1111/jnc.12345