UMLS:C0030567 - FACTA Search

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Query: UMLS:C0030567 (Parkinson's disease)
63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The simplest explanation for the selective loss of substantia nigra (SN) dopamine (DA) neurons in Parkinson's disease (PD) is that DA or a metabolite is neurotoxic. Recently, a series of investigations implicate the MAO metabolite of DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL), as the critical endogenous toxin which triggers DA neuron loss in PD: 1. Hereditary PD contains mutations in the gene for alpha-synuclein (alpha-syn). Investigations implicate a DA metabolite as mediator of alpha-syn neurotoxicity, and DOPAL is 1000-fold more toxic than DA in vivo. 2. A deficit in mitochondrial complex I is found in PD SN. Inhibition of complex I causes increases in DOPAL levels and death of DA neurons in vitro and in vivo. 3. L-DOPA, the precursor of DA, which is used to treat PD, is toxic and contributes to the progression of PD. L-DOPA-treated rats have an 18-fold increase in striatal DOPAL. 4. Free hydroxyl radicals (.OH) trigger aggregation of alpha-syn to its toxic form. DOPAL with H(2)O(2) generates.OH radicals. These investigations provide several therapeutic strategies to limit DOPAL toxicity and progression of PD: 1. Delaying the start of L-DOPA therapy by early use of DA receptor agonists, which may also be free radical scavengers, limits the amount of DOPAL formed from L-DOPA. 2. Nonspecific MAO inhibitors may more effectively decrease production of DOPAL from DA than MAO-B inhibitors. 3. Newer more potent and targeted free radical scavengers could block DOPAL toxicity. 4. Coenzyme Q(10) increases complex I activity and nicotine adenine dinucleotide (NAD) synthesis, and thereby could enhance DOPAL catabolism by aldehyde dehydrogenase, which uses NAD as a cofactor. 5. DA uptake blockers could be used to limit intraneuronal DOPAL production. 6. Tauroursodeoxycholic acid, an inhibitor of apoptosis shown to be effective in models of Huntington's disease, may also prove effective in blocking DOPAL toxicity in PD. 7. Agents which block aggregation of alpha-syn should limit DOPAL toxicity.
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PMID:3,4-dihydroxyphenylacetaldehyde: a potential target for neuroprotective therapy in Parkinson's disease. 1276 6

Dopamine (DA) neurons degenerate in Parkinson's disease and dopamine neurotransmission may be affected in psychotic states seen in schizophrenia. Understanding the regulation of enzymes involved in DA metabolism may therefore lead to new treatment strategies for these severe conditions. We investigated mRNA expression of the cytosolic aldehyde dehydrogenase (ALDH1), presumably involved in DA degradation, by in situ hybridization in DA neurons of human postmortem material. Parallel labeling for GAPDH, neuron-specific enolase, tyrosine hydroxylase, dopamine transporter, and dopamine beta-hydroxylase was used to ensure suitability of tissue specimen and to identify all dopamine neurons. ALDH1 was found to be expressed highly and specifically in DA cells of both substantia nigra (SN) and the ventral tegmental area (VTA) of controls. A marked reduction of ALDH1 expression was seen in surviving neurons of SN pars compacta but not of those in the VTA in Parkinson's disease. In patients suffering from schizophrenia we found ALDH1 expression at normal levels in DA cells of SN but at significantly reduced levels in those of the VTA. We conclude that ALDH1 is strongly and specifically expressed in human mesencephalic dopamine neurons and that low levels of ALDH1 expression correlate with DA neuron dysfunction in the two investigated human conditions.
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PMID:ALDH1 mRNA: presence in human dopamine neurons and decreases in substantia nigra in Parkinson's disease and in the ventral tegmental area in schizophrenia. 1467 78

Lipid peroxidation and mitochondrial dysfunction are associated with multiple neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. 4-Hydroxy-trans-2-nonenal (HNE) is a major, neurotoxic product of lipid peroxidation whose levels are elevated in these diseases. Previous data from this laboratory demonstrate that mitochondria play an important role in the detoxification of HNE particularly through the oxidation of HNE to 4-hydroxy-trans-2-nonenoate (HNEAcid). In this work, we examined the disposition of HNE when incubated with intact, well-coupled, rat brain mitochondria. Our results demonstrated that HNE loss occurred in a time- and concentration-dependent, saturable manner with a K(M) of 28.0 +/- 11.8 microM HNE and a V(Max) of 10.0 +/- 1.7 nmol/min/mg. HNEAcid formation occurred in a saturable manner with a K(M) of 25.3 +/- 6.3 microM HNE and a V(Max) of 4.4 +/- 0.43 nmol/min/mg. The formation of HNE-glutathione adducts and HNE-protein adducts comprised only a small percentage of HNE consumption. HNE metabolism was significantly diminished in rat brain mitochondria isolated from older animals. We then tested the hypothesis that the mitochondrial NADH/NAD(+) ratio regulated matrix aldehyde dehydrogenase activity. Our results demonstrate that HNE oxidation was significantly inhibited to a greater extent with pyruvate and malate as substrates vs succinate. Complex I inhibition with respiratory substrates further blocked HNE detoxification. Rotenone (100 nM) inhibited respiration by 15% whereas HNEAcid formation was decreased to 72% of control levels. These results demonstrate that in situ mitochondrial aldehyde detoxification is affected by decrements in NAD(+) availability and complex I activity.
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PMID:Metabolism of 4-hydroxy-trans-2-nonenal by central nervous system mitochondria is dependent on age and NAD+ availability. 1537 62

The A9 dopaminergic (DA) neuronal group projecting to the dorsal striatum is the most vulnerable in Parkinson's disease (PD). We genetically engineered mouse embryonic stem (ES) cells to express the transcription factors Nurr1 or Pitx3. After in vitro differentiation of Pitx3-expressing ES cells, the proportion of DA neurons expressing aldehyde dehydrogenase 2 (AHD2) increased, while the total number of DA neurons remained the same. The highest levels of AHD2 expression were observed in mouse A9 DA neurons projecting to the dorsal striatum. Furthermore, real-time PCR analyses of in vitro differentiated Pitx3-expressing ES cells revealed that genes highly expressed in A9 DA neurons were up-regulated. When transplanted into the mouse striatum, Pitx3-expressing cells generated an increased proportion of AHD2-expressing DA neurons. Contrastingly, in Nurr1-expressing ES cells, increases of all midbrain DA markers were observed, resulting in a higher total number of DA neurons in vitro and in vivo, whereas the proportion of AHD2-expressing DA neurons was not changed. Our data, using gain-of-function analysis of ES cells, suggest that Pitx3 may be important for specification and/or maintenance of A9-like neuronal properties, while Nurr1 influences overall midbrain DA specification. These findings may be important for modifying ES cells to generate an optimal cell source for transplantation therapy of PD.
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PMID:The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons. 1569 6

Recent evidence indicates a role for oxidative stress and resulting products, e.g. 4-hydroxy-2-nonenal (4HNE) in the pathogenesis of Parkinson's disease (PD). 4HNE is a known inhibitor of mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme very important to the dopamine (DA) metabolic pathway. DA undergoes monoamine oxidase-catalyzed oxidative deamination to 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is metabolized primarily to 3,4-dihydroxyphenylacetic acid (DOPAC) via ALDH2. The biotransformation of DOPAL is critical as previous studies have demonstrated this DA-derived aldehyde to be a reactive electrophile and toxic to dopaminergic cells. Therefore, 4HNE produced via oxidative stress may inhibit ALDH2-mediated oxidation of the endogenous neurotoxin DOPAL. To test this hypothesis, ALDH2 in various model systems was treated with 4HNE and activity toward DOPAL measured. Incubation of human recombinant ALDH2 with 4HNE (1.5-30 microM) yielded inhibition of activity toward DOPAL. Furthermore, ALDH2 in rat brain mitochondrial lysate as well as isolated rat brain mitochondria was also sensitive to the lipid peroxidation product at low micromolar, as evident by a decrease in the rate of DOPAL to DOPAC conversion measured using HPLC. Taken together, these data indicate that 4HNE at low micromolar inhibits mitochondrial biotransformation of DOPAL to DOPAC, and generation of the lipid peroxidation product may represent a mechanism yielding aberrant levels of DOPAL, thus linking oxidative stress to the uncontrolled production of an endogenous neurotoxin relevant to PD.
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PMID:Inhibition of the oxidative metabolism of 3,4-dihydroxyphenylacetaldehyde, a reactive intermediate of dopamine metabolism, by 4-hydroxy-2-nonenal. 1695 64

Among the several converging factors leading to Parkinson's disease, epidemiological studies indicate a correlation between Parkinson's disease (PD) with living in a rural area and/or exposure to agricultural pesticides. In this present study, we examined the potential of multiple agricultural pesticides for their ability to inhibit the function of whole, respiring rat brain mitochondria using the oxidation of the neurotoxic lipid-aldehyde trans-4-hydroxy-2-nonenal (HNE) as a biomarker for mitochondrial aldehyde dehydrogenase (ALDH) activity in situ. We chose an arbitrary cutoff concentration of 10 microM of each pesticide. Our data demonstrate that only four of the eighteen compounds tested inhibited oxidation of HNE to trans-4-hydroxy-2-nonenoic acid (HNEAcid). These compounds included rotenone, maneb, mancozeb, and benomyl. Surprisingly, maneb, mancozeb, and benomyl did not inhibit mitochondrial respiration but inhibited the activity of purified rat ALDH2 and rat ALDH5A, enzymes found in brain mitochondria that oxidize HNE and aldehydes derived from neurotransmitters. Our data demonstrate that mitochondrial ALDHs are sensitive targets of pesticide inactivation and that pesticides such as maneb and benomyl can decrease the detoxification of lipid peroxidation derived aldehydes such as HNE and, likely, aldehydes derived from neurotransmitters.
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PMID:Inhibition of aldehyde detoxification in CNS mitochondria by fungicides. 1701 Apr 40

In neurodegenerative diseases augmented polyamine metabolism results in the generation of hydrogen peroxide and a number of reactive aldehydes that participate in the death of compromised tissue. The major aldehydes produced by polyamine oxidase and amine oxidases include the 2-alkenal acrolein, the acetoamidoaldehyde 3-acetamidopropanal (3-AAP) and the aminoaldehydes 3-aminopropanal (3-AP) and 4-aminobutanal (4-AB). Using retinal ganglion cell (E1A-NR.3) cultures, we confirmed the cytotoxicity of acrolein and 3-AP. For the first time we also demonstrated the cytotoxicity of 4-AB and the lack of toxicity of 3-AAP. Our data with 3-AAP, a product of N-acetylspermine and N-acetylspermidine metabolism, indicate that the aldehyde function of aminoaldehydes is insufficient to express toxicity since the free amino group of aminoaldehydes is also required to gain access to lysosomes where their cytotoxic actions are expressed via leakage of cathepsins that compromise mitochondrial integrity. Metabolism of 3-AP to beta-alanine by aldehyde dehydrogenase was also evaluated in retinal ganglion cell cultures and found to proceed at a linear rate of 24.3+/-1 nmol/mg protein/h. These are the first data demonstrating the dynamic cellular detoxification of 3-AP by neural cells and support the concept that decrements in aldehyde elimination leading to an increase in "aldehyde load" may play pivotal roles in the development and progression of neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis and Parkinson's disease.
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PMID:The concept of "aldehyde load" in neurodegenerative mechanisms: cytotoxicity of the polyamine degradation products hydrogen peroxide, acrolein, 3-aminopropanal, 3-acetamidopropanal and 4-aminobutanal in a retinal ganglion cell line. 1736 87

Recent work indicates that oxidative stress is a factor in Parkinson's disease (PD); however, it is unknown how this condition causes selective dopaminergic cell death. The neurotransmitter dopamine (DA) has been implicated as an endogenous neurotoxin to explain the selective neurodegeneration. DA undergoes catabolism by monoamine oxidase (MAO) to the reactive intermediate 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is further oxidized to 3,4-dihydroxyphenylacetic (DOPAC) acid via mitochondrial aldehyde dehydrogenase (ALDH). Previous studies found DOPAL to be more toxic than DA, and the major lipid peroxidation products, that is, 4-hydroxynonenal (4HNE) and malondialdehyde (MDA), potently inhibit ALDH. The hypothesis of this work is that lipid peroxidation products inhibit DOPAL oxidation, yielding aberrant levels of the reactive aldehyde intermediate. Treatment of striatal synaptosomes with 2-100 microM 4HNE or 2-50 microM MDA impaired DOPAL oxidation, resulting in elevated [DOPAL]. The aberrant concentration of DOPAL yielded an increase in protein modification by the DA-derived aldehyde, evident via staining of proteins with nitroblue tetrazolium (NBT). Pretreatment of synaptosomes with an MAO inhibitor significantly decreased NBT staining. On the basis of NBT staining, the order of protein reactivity for DA and metabolites was found to be DOPAL>>DOPAC>DA. Mass spectrometric analysis of a model peptide reacted with DOPAL revealed the adduct to be a Schiff base product. In summary, these data demonstrate the sensitivity of DA catabolism to the lipid peroxidation products 4HNE and MDA even at low, physiologic levels and suggest a mechanistic link between oxidative stress and generation of aberrant levels of an endogenous and protein reactive dopaminergic toxin relevant to PD.
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PMID:Lipid peroxidation products inhibit dopamine catabolism yielding aberrant levels of a reactive intermediate. 1788 26

Dopamine (DA) has been implicated as an endogenous neurotoxin to explain the selective neurodegeneration as observed for Parkinson's disease (PD). In addition, oxidative stress and lipid peroxidation are hypothesized culprits in PD pathogenesis. DA undergoes catabolism by monoamine oxidase (MAO) to 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is further oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) via aldehyde dehydrogenase (ALDH). As a minor and compensatory metabolic pathway, DOPAL can be reduced to 3,4-dihydroxyphenylethanol (DOPET) via cytosolic aldehyde or aldose reductase (AR). Previous studies have found DOPAL to be significantly more toxic to DA cells than DA and that the major lipid peroxidation products, that is, 4-hydroxynonenal (4HNE) and malondialdehyde (MDA), potently inhibit DOPAL oxidation via ALDH. The hypothesis of this work is that lipid peroxidation products inhibit DOPAL oxidation, yielding aberrant levels of the toxic aldehyde intermediate. To test this hypothesis, nerve growth factor-differentiated PC6-3 cells were used as a model for DA neurons. Cell viability in the presence of 4HNE and MDA (2-100 microM) was measured by MTT assay, and it was found that only 100 microM 4HNE exhibited significant cytotoxicity. Treatment of cells with varying concentrations of 4HNE and MDA resulted in reduced DOPAC production and significant elevation of DOPAL levels, suggesting inhibition of ALDH. In cells treated with 4HNE that exhibited elevated DOPAL, there was a significant increase in DOPET. However, elevated DOPET was not observed for the cells treated with MDA, suggesting MDA to be an inhibitor of AR. Using isolated cytosolic AR, it was found that MDA but not 4HNE inhibited reductase activity toward DOPAL, surprisingly. These data demonstrate that the oxidative stress products 4HNE and MDA inhibit the aldehyde biotransformation step of DA catabolism yielding elevated levels of the endogenous neurotoxin DOPAL, which may link oxidative stress to selective neurodegeneration as seen in PD.
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PMID:Products of oxidative stress inhibit aldehyde oxidation and reduction pathways in dopamine catabolism yielding elevated levels of a reactive intermediate. 1938 87

Dopamine (DA) undergoes monoamine oxidase catalyzed oxidative deamination to 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is metabolized primarily to 3,4-dihydroxyphenylacetic acid (DOPAC) via aldehyde dehydrogenase (ALDH). Previous studies demonstrated DOPAL to be neurotoxic, more so than DA and other metabolites, and implicated the aldehyde intermediate as a factor in the pathogenesis of Parkinson's disease (PD). However, the mechanism for generation of DOPAL at aberrant levels and the pathways for toxicity are not conclusively known. Various models for DA catabolism revealed the susceptibility of DOPAL biotransformation (e.g., ALDH) to products of oxidative stress, e.g., 4-hydroxy-2-nonenal, at physiologic/pathologic levels and agents that induce oxidative stress. An elevated concentration of DOPAL correlated with increased protein modification with subsequent work demonstrating significant reactivity of the DA-derived electrophile toward protein nucleophiles compared to DA and other metabolites, e.g., DOPAC. The addition of DOPAL to proteins proceeds via reaction of the aldehyde with Lys residues, yielding a Schiff base; however, post-adduction chemistry occurs for the DOPAL-modification resulting in protein cross-linking. Preliminary work indicates enzymes in DA synthesis and catabolism to be cellular targets for DOPAL. Functional consequences for elevated levels of the DA-derived aldehyde and protein modification may include adverse cellular effects. These data implicate DOPAL as a toxic and reactive intermediate potentially serving as a "chemical trigger" for some stage of PD pathogenesis.
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PMID:Dopamine-derived biological reactive intermediates and protein modifications: Implications for Parkinson's disease. 2123 38

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