Impaired dopamine metabolism in Parkinson’s disease pathogenesis
Abstract A full understanding of Parkinson’s Disease etiopathogenesis and of the causes of the preferential vulnerability of nigrostriatal dopaminergic neurons is still an unsolved puzzle. A multiple-hit hypothesis has been proposed, which may explain the convergence of familial, environmental and i...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-08-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13024-019-0332-6 |
| _version_ | 1818048586738302976 |
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| author | Anna Masato Nicoletta Plotegher Daniela Boassa Luigi Bubacco |
| author_facet | Anna Masato Nicoletta Plotegher Daniela Boassa Luigi Bubacco |
| author_sort | Anna Masato |
| collection | DOAJ |
| description | Abstract A full understanding of Parkinson’s Disease etiopathogenesis and of the causes of the preferential vulnerability of nigrostriatal dopaminergic neurons is still an unsolved puzzle. A multiple-hit hypothesis has been proposed, which may explain the convergence of familial, environmental and idiopathic forms of the disease. Among the various determinants of the degeneration of the neurons in Substantia Nigra pars compacta, in this review we will focus on the endotoxicity associated to dopamine dyshomeostasis. In particular, we will discuss the relevance of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) in the catechol-induced neurotoxicity. Indeed, the synergy between the catechol and the aldehyde moieties of DOPAL exacerbates its reactivity, resulting in modification of functional protein residues, protein aggregation, oxidative stress and cell death. Interestingly, αSynuclein, whose altered proteostasis is a recurrent element in Parkinson’s Disease pathology, is considered a preferential target of DOPAL modification. DOPAL triggers αSynuclein oligomerization leading to synapse physiology impairment. Several factors can be responsible for DOPAL accumulation at the pre-synaptic terminals, i.e. dopamine leakage from synaptic vesicles, increased rate of dopamine conversion to DOPAL by upregulated monoamine oxidase and decreased DOPAL degradation by aldehyde dehydrogenases. Various studies report the decreased expression and activity of aldehyde dehydrogenases in parkinsonian brains, as well as genetic variants associated to increased risk in developing the pathology. Thus, we discuss how the deregulation of these enzymes might be considered a contributing element in the pathogenesis of Parkinson’s Disease or a down-stream effect. Finally, we propose that a better understanding of the impaired dopamine metabolism in Parkinson’s Disease would allow a more refined patients stratification and the design of more targeted and successful therapeutic strategies. |
| first_indexed | 2024-12-10T10:24:03Z |
| format | Article |
| id | doaj.art-0cf230b6e75f41fe80090eaf93b13ea6 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-10T10:24:03Z |
| publishDate | 2019-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-0cf230b6e75f41fe80090eaf93b13ea62022-12-22T01:52:46ZengBMCMolecular Neurodegeneration1750-13262019-08-0114112110.1186/s13024-019-0332-6Impaired dopamine metabolism in Parkinson’s disease pathogenesisAnna Masato0Nicoletta Plotegher1Daniela Boassa2Luigi Bubacco3Department of Biology, University of PadovaDepartment of Biology, University of PadovaDepartment of Neurosciences, and National Center for Microscopy and Imaging Research, University of California San DiegoDepartment of Biology, University of PadovaAbstract A full understanding of Parkinson’s Disease etiopathogenesis and of the causes of the preferential vulnerability of nigrostriatal dopaminergic neurons is still an unsolved puzzle. A multiple-hit hypothesis has been proposed, which may explain the convergence of familial, environmental and idiopathic forms of the disease. Among the various determinants of the degeneration of the neurons in Substantia Nigra pars compacta, in this review we will focus on the endotoxicity associated to dopamine dyshomeostasis. In particular, we will discuss the relevance of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) in the catechol-induced neurotoxicity. Indeed, the synergy between the catechol and the aldehyde moieties of DOPAL exacerbates its reactivity, resulting in modification of functional protein residues, protein aggregation, oxidative stress and cell death. Interestingly, αSynuclein, whose altered proteostasis is a recurrent element in Parkinson’s Disease pathology, is considered a preferential target of DOPAL modification. DOPAL triggers αSynuclein oligomerization leading to synapse physiology impairment. Several factors can be responsible for DOPAL accumulation at the pre-synaptic terminals, i.e. dopamine leakage from synaptic vesicles, increased rate of dopamine conversion to DOPAL by upregulated monoamine oxidase and decreased DOPAL degradation by aldehyde dehydrogenases. Various studies report the decreased expression and activity of aldehyde dehydrogenases in parkinsonian brains, as well as genetic variants associated to increased risk in developing the pathology. Thus, we discuss how the deregulation of these enzymes might be considered a contributing element in the pathogenesis of Parkinson’s Disease or a down-stream effect. Finally, we propose that a better understanding of the impaired dopamine metabolism in Parkinson’s Disease would allow a more refined patients stratification and the design of more targeted and successful therapeutic strategies.http://link.springer.com/article/10.1186/s13024-019-0332-6Parkinson’s diseaseSelective vulnerabilityDopamineDOPALαSynucleinAldehyde dehydrogenase |
| spellingShingle | Anna Masato Nicoletta Plotegher Daniela Boassa Luigi Bubacco Impaired dopamine metabolism in Parkinson’s disease pathogenesis Molecular Neurodegeneration Parkinson’s disease Selective vulnerability Dopamine DOPAL αSynuclein Aldehyde dehydrogenase |
| title | Impaired dopamine metabolism in Parkinson’s disease pathogenesis |
| title_full | Impaired dopamine metabolism in Parkinson’s disease pathogenesis |
| title_fullStr | Impaired dopamine metabolism in Parkinson’s disease pathogenesis |
| title_full_unstemmed | Impaired dopamine metabolism in Parkinson’s disease pathogenesis |
| title_short | Impaired dopamine metabolism in Parkinson’s disease pathogenesis |
| title_sort | impaired dopamine metabolism in parkinson s disease pathogenesis |
| topic | Parkinson’s disease Selective vulnerability Dopamine DOPAL αSynuclein Aldehyde dehydrogenase |
| url | http://link.springer.com/article/10.1186/s13024-019-0332-6 |
| work_keys_str_mv | AT annamasato impaireddopaminemetabolisminparkinsonsdiseasepathogenesis AT nicolettaplotegher impaireddopaminemetabolisminparkinsonsdiseasepathogenesis AT danielaboassa impaireddopaminemetabolisminparkinsonsdiseasepathogenesis AT luigibubacco impaireddopaminemetabolisminparkinsonsdiseasepathogenesis |