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

Abstract

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.

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

“…The increased DOPAC levels suggest that 1-octen-3-ol may interfere with the packaging of dopamine into synaptic vesicles, which increases autooxidation of dopamine and generation of oxidative damage and reactive dopamine metabolites such as 3,4-dihydroxyphenylacetaldehyde (36)(37)(38). Indeed, we previously found that an increase in reactive oxygen species is observed in head extracts from 1-octen-3-ol-exposed flies (16).…”

Oligomerization and Membrane-binding Properties of Covalent Adducts Formed by the Interaction of α-Synuclein with the Toxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL)

“…For production of 15 N-aS or 13 C, 15 N-aS, cells were grown in minimal media containing 15 N-labeled ammonium chloride or 15 Nlabeled ammonium chloride plus 13 C-labeled glucose, respectively, and the protein expression was induced with 0.8 mM isopropyl 1-thio-␤-D-galactopyranoside for 4 h at 37°C.…”

“…Amide resonance assignments were performed according to previously reported chemical shift assignments for intrinsically unfolded aS (20 -22). HNCA experiments of SDS-bound 13 C, 15 N-aS provided ␣-carbon chemical shifts for secondary shift analysis. For this experiment, 40 mM deuterated SDS was added to 200 M doublelabeled aS-unmodified (aS unmod ) or aS-DOPAL(1:10) monomer.…”

“…Elevated DOPAL levels in PD are suggested to result from a combination of decreased vesicular uptake of cytosolic DA (decreased by ϳ89%) and decreased DOPAL detoxification by the enzyme aldehyde dehydrogenase (ALDH) (decreased by 70%) (13), which converts DOPAL to its non-toxic metabolite 3,4-dihydroxyphenylacetic acid. Interestingly, the inhibition of ALDH is sufficient to cause a parkinsonian phenotype in mice (14).…”

Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo

“…VMAT2 is an H + -ATPase antiporter, which uses the vesicular electrochemical gradient to drive the packaging of cytosolic transmitter into small synaptic and dense core vesicles (8)(9)(10). VMAT2 is also essential for survival of dopamine neurons as cytosolic dopamine is neurotoxic (11,12). By sequestering intracellular dopamine into vesicles, VMAT2 prevents cytosolic dopamine accumulation and its subsequent conversion to neurotoxic species (13)(14)(15)(16)(17).…”