Prospects for the Development of Pink1 and Parkin Activators for the Treatment of Parkinson’s Disease
Abstract
:1. Introduction
2. General Mechanism of Mitophagy
3. The Role of Mitophagy Disorders in the Development of Parkinson’s Disease
4. Features of Pink1 and Parkin as Targets for the Therapy of Parkinson’s Disease
4.1. Characterized Mutant Forms of Mitophagy Proteins
4.2. Level of Expression of Mitophagy Proteins in Neurons
4.3. Labeled Cellular Localization of Mitophagy Proteins
5. Current State of Development of Pink1 and Parkin Activators
6. Evaluation of the Prospects for the Development of Pink1 and Parkin Activators for the Treatment of Parkinson’s Disease
7. Discussion
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Protein | Mutation or Modification | Pathological Mechanism |
---|---|---|
Pink1 | I368N | Impossibility of binding to the outer mitochondrial membrane |
Pink1 | p.Q456X | Decreasing of mRNA level |
Pink1 | p.G411S | Partial loss of kinase activity |
Parkin | UBL domain (1) | Decrease in Parkin phosphorylation |
Parkin | UBL domain (2) | Parkin degradation |
Pink1 | S-nitrosylation | Loss of kinase activity |
Pink1 | G309D | Accumulation of α-synuclein |
Therapeutic Compound | Therapeutic Strategy | Therapeutic Mechanism |
---|---|---|
Kinetin | PINK1 activator | Direct binding to the active site |
Celastrol | PINK1 activator | Enhancing expression |
Salidroside | PINK1 activator | Enhancing expression |
No name | Parkin activator | Direct binding to the active site |
USP30i | USP30 inhibitor | Direct binding to the active site |
Factor | Advantages | Disadvantages |
---|---|---|
Investment attractiveness | Approximately 5–10% of PD patients have monogenic forms of the disease. Mutations encoding genes in Pink1 and/or Parkin account for 1–9% of all genetic PD. Therefore, considering the low percentage of subjects bearing these mutations, it does not seem very attractive to invest money and time in the development of novel activators of mitophagy. | |
State of Development | Studies have shown the ability of potential drugs to reduce neuronal degeneration, which is a prerequisite for efficacy in the treatment of PD. |
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Choice of active compound |
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Target selection |
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Blagov, A.V.; Goncharov, A.G.; Babich, O.O.; Larina, V.V.; Orekhov, A.N.; Melnichenko, A.A. Prospects for the Development of Pink1 and Parkin Activators for the Treatment of Parkinson’s Disease. Pharmaceutics 2022, 14, 2514. https://doi.org/10.3390/pharmaceutics14112514
Blagov AV, Goncharov AG, Babich OO, Larina VV, Orekhov AN, Melnichenko AA. Prospects for the Development of Pink1 and Parkin Activators for the Treatment of Parkinson’s Disease. Pharmaceutics. 2022; 14(11):2514. https://doi.org/10.3390/pharmaceutics14112514
Chicago/Turabian StyleBlagov, Alexander V., Andrey G. Goncharov, Olga O. Babich, Viktoriya V. Larina, Alexander N. Orekhov, and Alexandra A. Melnichenko. 2022. "Prospects for the Development of Pink1 and Parkin Activators for the Treatment of Parkinson’s Disease" Pharmaceutics 14, no. 11: 2514. https://doi.org/10.3390/pharmaceutics14112514