Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons
Parkinson’s disease (PD) is one of the key neurodegenerative disorders caused by a dopamine deficiency in the striatum due to the death of dopaminergic (DA) neurons of the substantia nigra pars compacta. The initially discovered A53T mutation in the alpha-synuclein gene was linked to the formation o...
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MDPI AG
2022-09-01
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| Series: | Biomedicines |
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| author | Valeria V. Goloborshcheva Valerian G. Kucheryanu Natalia A. Voronina Ekaterina V. Teterina Aleksey A. Ustyugov Sergei G. Morozov |
| author_facet | Valeria V. Goloborshcheva Valerian G. Kucheryanu Natalia A. Voronina Ekaterina V. Teterina Aleksey A. Ustyugov Sergei G. Morozov |
| author_sort | Valeria V. Goloborshcheva |
| collection | DOAJ |
| description | Parkinson’s disease (PD) is one of the key neurodegenerative disorders caused by a dopamine deficiency in the striatum due to the death of dopaminergic (DA) neurons of the substantia nigra pars compacta. The initially discovered A53T mutation in the alpha-synuclein gene was linked to the formation of cytotoxic aggregates: Lewy bodies in the DA neurons of PD patients. Further research has contributed to the discovery of beta- and gamma-synucleins, which presumably compensate for the functional loss of either member of the synuclein family. Here, we review research from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity models and various synuclein-knockout animals. We conclude that the differences in the sensitivity of the synuclein-knockout animals compared with the MPTP neurotoxin are due to the ontogenetic selection of early neurons followed by a compensatory effect of beta-synuclein, which optimizes dopamine capture in the synapses. Triple-knockout synuclein studies have confirmed the higher sensitivity of DA neurons to the toxic effects of MPTP. Nonetheless, beta-synuclein could modulate the alpha-synuclein function, preventing its aggregation and loss of function. Overall, the use of knockout animals has helped to solve the riddle of synuclein functions, and these proteins could be promising molecular targets for the development of therapies that are aimed at optimizing the synaptic function of dopaminergic neurons. |
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| last_indexed | 2024-03-10T00:38:15Z |
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| series | Biomedicines |
| spelling | doaj.art-4a66804b54b74513b1d7d09f95e814d32023-11-23T15:12:07ZengMDPI AGBiomedicines2227-90592022-09-01109227810.3390/biomedicines10092278Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic NeuronsValeria V. Goloborshcheva0Valerian G. Kucheryanu1Natalia A. Voronina2Ekaterina V. Teterina3Aleksey A. Ustyugov4Sergei G. Morozov5Institute of General Pathology and Pathophysiology, 125315 Moscow, RussiaInstitute of General Pathology and Pathophysiology, 125315 Moscow, RussiaInstitute of General Pathology and Pathophysiology, 125315 Moscow, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, RussiaInstitute of General Pathology and Pathophysiology, 125315 Moscow, RussiaParkinson’s disease (PD) is one of the key neurodegenerative disorders caused by a dopamine deficiency in the striatum due to the death of dopaminergic (DA) neurons of the substantia nigra pars compacta. The initially discovered A53T mutation in the alpha-synuclein gene was linked to the formation of cytotoxic aggregates: Lewy bodies in the DA neurons of PD patients. Further research has contributed to the discovery of beta- and gamma-synucleins, which presumably compensate for the functional loss of either member of the synuclein family. Here, we review research from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity models and various synuclein-knockout animals. We conclude that the differences in the sensitivity of the synuclein-knockout animals compared with the MPTP neurotoxin are due to the ontogenetic selection of early neurons followed by a compensatory effect of beta-synuclein, which optimizes dopamine capture in the synapses. Triple-knockout synuclein studies have confirmed the higher sensitivity of DA neurons to the toxic effects of MPTP. Nonetheless, beta-synuclein could modulate the alpha-synuclein function, preventing its aggregation and loss of function. Overall, the use of knockout animals has helped to solve the riddle of synuclein functions, and these proteins could be promising molecular targets for the development of therapies that are aimed at optimizing the synaptic function of dopaminergic neurons.https://www.mdpi.com/2227-9059/10/9/2278synucleinsdopaminergic neuronMPTPknockout miceParkinson’s disease |
| spellingShingle | Valeria V. Goloborshcheva Valerian G. Kucheryanu Natalia A. Voronina Ekaterina V. Teterina Aleksey A. Ustyugov Sergei G. Morozov Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons Biomedicines synucleins dopaminergic neuron MPTP knockout mice Parkinson’s disease |
| title | Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons |
| title_full | Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons |
| title_fullStr | Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons |
| title_full_unstemmed | Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons |
| title_short | Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons |
| title_sort | synuclein proteins in mptp induced death of substantia nigra pars compacta dopaminergic neurons |
| topic | synucleins dopaminergic neuron MPTP knockout mice Parkinson’s disease |
| url | https://www.mdpi.com/2227-9059/10/9/2278 |
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