Decreased vesicular storage and aldehyde dehydrogenase activity in multiple system atrophy

Abstract

Background: Parkinson disease (PD) and multiple system atrophy (MSA) share some neuropathologic features (nigrostriatal dopaminergic lesion, alpha-synuclein deposition) but not others (Lewy bodies in PD, glial cytoplasmic inclusions in MSA). In PD evidence has accrued for a vesicular storage defect and decreased aldehyde dehydrogenase (ALDH) activity in residual dopaminergic terminals, resulting in accumulation of the toxic dopamine (DA) metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). In this study we asked whether MSA entails a similar abnormal neurochemical pattern.

Methods: DA and its main neuronal metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), norepinephrine (NE) and its main neuronal metabolite 3,4-dihydroxyphenylglycol (DHPG), the catecholamine precursor DOPA, and DOPAL were measured in striatal and frontal cortical tissue from patients with pathologically proven end-stage MSA (N = 15), sporadic PD (N = 17), and control subjects (N = 18).

Results: Compared to the control group, the MSA and PD groups had similarly decreased putamen DA (by 96% and 93%, p < 0.0001), DOPAC (97% and 95%, p < 0.0001), NE (91% and 74%, p < 0.0001), and DHPG (81% and 74%, p < 0.0001). In the MSA and PD groups, ratios of DOPAL:DA were 2.3 and 3.5 times control and DHPG:NE 3.1 and 2.6 times control, while DOPAC:DOPAL ratios were decreased by 61% and 74%. In both diseases cortical NE and DHPG were decreased, while DA and DOPAC were not.

Conclusions: MSA and PD entail a catecholamine metabolic profile indicating impaired vesicular storage, decreased ALDH activity, and DOPAL buildup, which might be part of a common pathway in catecholamine neuronal death. Targeting this pathway by interfering with catecholaldehyde production or effects constitutes a novel treatment approach.

Keywords: DOPAL; Dopamine; Multiple system atrophy; Norepinephrine; Parkinson disease; Putamen.

Figure 1

Diagrams of the synthesis and fate of dopamine (DA) and norepinephrine (NE). DA that leaks from vesicles (V) into the cytoplasm (C) or that is taken up via the cell membrane dopamine transporter (DAT) and escapes vesicular reuptake via the vesicular monoamine transporter (VMAT) is subject to oxidative deamination catalyzed by monoamine oxidase (MAO) to form the catecholaldehyde, dihydroxyphenylacetaldehyde (DOPAL). DOPAL is metabolized by aldehyde dehydrogenase (ALDH) to form dihydroxyphenylacetic acid (DOPAC), the major metabolic route, or aldehyde/aldose reductase (AR) to form dihydroxyphenylethanol (DOPET), the minor metabolic route. In contrast, the catecholaldehyde formed from NE, dihydroxyphenylglycolaldehyde (DOPEGAL), is detoxified mainly by AR to form dihydroxyphenylglycol (DHPG). Dihydroxymandelic acid (DHMA) is a minor NE metabolite. Other abbreviations: NET=cell membrane norepinephrine transporter.

Figure 2

Mean (± SEM) and individual values for putamen tissue concentrations of (A) DA and DOPAC and (B) NE and DHPG in patients with multiple system atrophy (blue), Parkinson disease (red), or control subjects (gray).

Figure 3

Scatter plot relating putamen tissue NE to DA in patients with multiple system atrophy (blue), Parkinson disease (red), or control subjects (gray).

Figure 4

Mean (± SEM) values for putamen tissue concentration ratios of DA:DOPA, DHPG:NE, and DOPAC:DOPAL in patients with multiple system atrophy (blue), Parkinson disease (red), or control subjects (gray).