| Abstract | The molecular mechanisms causing the loss of dopaminergic neurons containing neuromelanin in the substantia nigra and responsible for motor symptoms of Parkinson's disease are still unknown. The discovery of genes associated with Parkinson's disease (such as alpha synuclein (SNCA), E3 ubiquitin protein ligase (parkin), DJ-1 (PARK7), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL-1), serine/threonine-protein kinase (PINK-1), leucine-rich repeat kinase 2 (LRRK2), cation-transporting ATPase 13A1 (ATP13A), etc.) contributed enormously to basic research towards understanding the role of these proteins in the sporadic form of the disease. However, it is generally accepted by the scientific community that mitochondria dysfunction, alpha synuclein aggregation, dysfunction of protein degradation, oxidative stress and neuroinflammation are involved in neurodegeneration. Dopamine oxidation seems to be a complex pathway in which dopamine o-quinone, aminochrome and 5,6-indolequinone are formed. However, both dopamine o-quinone and 5,6-indolequinone are so unstable that is difficult to study and separate their roles in the degenerative process occurring in Parkinson's disease. Dopamine oxidation to dopamine o-quinone, aminochrome and 5,6-indolequinone seems to play an important role in the neurodegenerative processes of Parkinson's disease as aminochrome induces: (i) mitochondria dysfunction, (ii) formation and stabilization of neurotoxic protofibrils of alpha synuclein, (iii) protein degradation dysfunction of both proteasomal and lysosomal systems and (iv) oxidative stress. The neurotoxic effects of aminochrome in dopaminergic neurons can be inhibited by: (i) preventing dopamine oxidation of the transporter that takes up dopamine into monoaminergic vesicles with low pH and dopamine oxidative deamination catalyzed by monoamino oxidase (ii) dopamine o-quinone, aminochrome and 5,6-indolequinone polymerization to neuromelanin and (iii) two-electron reduction of aminochrome catalyzed by DT-diaphorase. Furthermore, dopamine conversion to NM seems to have a dual role, protective and toxic, depending mostly on the cellular context. |
| Text | 284594 2014 10.1111/jnc.12686 ISI Web of Science WOS 000337760500002 PubMed 24548101 5 6 indolequinone aminochrome dopamine dopamine o quinone neurodegeneration neuromelanin Parkinson s disease Protective and toxic roles of dopamine in Parkinson s disease Segura Aguilar J.; Paris I.; Muñoz P.; Ferrari E.; Zecca L.; Zucca F.A. Segura Aguilar, Juan; Paris, Irmgard; Muñoz, Patricia Faculty of Medicine, Molecular and Clinical Pharmacology, ICBM, University of Chile, Santiago, Chile; Paris, Irmgard Departamento de Ciencias Basicas, Facultad de Ciencias, Universidad Santo Tomas, Chile; Ferrari, Emanuele; Zecca, Luigi; Zucca, Fabio A. Institute of Biomedical Technologies National Research Council of Italy, Segrate, Milan, Italy. Segura Agular, J reprint author , Faculty of Medicine, Molecular and Clinical Pharmacology, ICBM, Santiago, Chile; e mail jsegura@med.uchile.cl The molecular mechanisms causing the loss of dopaminergic neurons containing neuromelanin in the substantia nigra and responsible for motor symptoms of Parkinson s disease are still unknown. The discovery of genes associated with Parkinson s disease such as alpha synuclein SNCA , E3 ubiquitin protein ligase parkin , DJ 1 PARK7 , ubiquitin carboxyl terminal hydrolase isozyme L1 UCHL 1 , serine/threonine protein kinase PINK 1 , leucine rich repeat kinase 2 LRRK2 , cation transporting ATPase 13A1 ATP13A , etc. contributed enormously to basic research towards understanding the role of these proteins in the sporadic form of the disease. However, it is generally accepted by the scientific community that mitochondria dysfunction, alpha synuclein aggregation, dysfunction of protein degradation, oxidative stress and neuroinflammation are involved in neurodegeneration. Dopamine oxidation seems to be a complex pathway in which dopamine o quinone, aminochrome and 5,6 indolequinone are formed. However, both dopamine o quinone and 5,6 indolequinone are so unstable that is difficult to study and separate their roles in the degenerative process occurring in Parkinson s disease. Dopamine oxidation to dopamine o quinone, aminochrome and 5,6 indolequinone seems to play an important role in the neurodegenerative processes of Parkinson s disease as aminochrome induces i mitochondria dysfunction, ii formation and stabilization of neurotoxic protofibrils of alpha synuclein, iii protein degradation dysfunction of both proteasomal and lysosomal systems and iv oxidative stress. The neurotoxic effects of aminochrome in dopaminergic neurons can be inhibited by i preventing dopamine oxidation of the transporter that takes up dopamine into monoaminergic vesicles with low pH and dopamine oxidative deamination catalyzed by monoamino oxidase ii dopamine o quinone, aminochrome and 5,6 indolequinone polymerization to neuromelanin and iii two electron reduction of aminochrome catalyzed by DT diaphorase. Furthermore, dopamine conversion to NM seems to have a dual role, protective and toxic, depending mostly on the cellular context. 129 Published version Publication date 2014 Jun. Epub 2014 Mar 18. Articolo in rivista Blackwell 0022 3042 Journal of neurochemistry Journal of neurochemistry J. neurochem. Journal of neurochemistry. JNC emanuele.ferrari FERRARI EMANUELE fabioandrea.zucca ZUCCA FABIO ANDREA luigi.zecca ZECCA LUIGI ME.P02.018.001 Invecchiamento e malattie neurodegenerative |
