Parkin-Mediated Mitophagy in Parkinson’s Disease
Introduction. Parkinson’s disease (PD) is a neurodegenerative that primarily affects movement due to the progressive reduction of dopaminergic neurons in the substantia nigra. The cause of death of these neurons is unknown but believed to involve both genetic and environmental factors.1 Although the incidence rate of PD increases with age with the mean onset at the age of 60, studies have shown a hereditary component in autosomal recessive juvenile parkinsonism (ARJP) with an onset of symptoms before the age of 40.2, 3 ARJP is associated with mutations in the Park2 gene can result in a dysfunctional Parkin protein, a ubiquitin ligase that interacts with PINK1 and results in the autophagy of impaired mitochondria (mitophagy).4 Studies have shown that the production of reactive oxygen species (ROS) can lead to the damage of mitochondria, which are normally degraded via mitophagy but accumulate and result in the eventual death of neurons in PINK1/Parkin mutations.5 Other studies indicate that the preventing the accumulation of ROS could be a potential therapeutic target.6 Methods. In vitro studies include purified protein constructs expressed in E. coli, transfection of HeLa cells, and neuronal cultures from embryonic mice. In vivo studies include mutant drosophila models. Data was collected via Western blot analysis, immunofluorescence imaging, and locomotion assays. Results. Substitution mutations were introduced to protein constructs and resulted in decreased phosphorylation efficiency to activate ubiquitin ligase activity.6 HeLa cells transfected with GFP-Parkin showed increased co-localization with mitochondrial markers in ROS-induced group compared to the rescue group with ROS scavengers.7 Drosophila brain specimens showed increased accumulation of ROS in PINK1/Parkin mutants along with climbing defects.8 Conclusions. The production of ROS can lead to the damage of mitochondria and the introduction ROS scavengers showed a significant decrease in Parkin recruitment for mitophagy by removing the initial injury and resulted in the survival of neurons. Furthermore, the ROS scavengers also demonstrated an improvement in function and could be a potential therapeutic target.
- Fox SH, Katzenschlager R, Lim S-Y, et al. International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinsons disease. Movement Disorders. 2018.
- Lang AE, Espay AJ. Disease modification in Parkinsons Disease: Current approaches, challenges, and future considerations. Movement Disorders. November 2018.
- Creed RB, Goldberg MS. New developments in genetic rat models of Parkinsons disease. Movement Disorders. August 2018.
- Um J-H, Yun J. Emerging role of mitophagy in human diseases and physiology. BMB Reports. 2017;50(6):299-307.
- Ashrafi G, Schlehe JS, Lavoie MJ, Schwarz TL. Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. The Journal of Cell Biology. 2014;206(5):655-670.
- Aguirre JD, Dunkerley KM, Lam R, Rusal M, Shaw GS. Impact of altered phosphorylation on loss of function of juvenile Parkinsonism-associated genetic variants of the E3 ligase parkin. Journal of Biological Chemistry. December 2018.
- Xiao B, Goh J-Y, Xiao L, Xian H, Lim K-L, Liou Y-C. Reactive oxygen species trigger Parkin/PINK1 pathway–dependent mitophagy by inducing mitochondrial recruitment of Parkin. Journal of Biological Chemistry. 2017;292(40):16697-16708.
- Biosa A, Sanchez-Martinez A, Filograna R, et al. Superoxide dismutating molecules rescue the toxic effects of PINK1 and parkin loss. Human Molecular Genetics. 2018;27(9):1618-1629.