Introduction. Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNPc) which leads to resting tremors, rigidity, akinesia, and postural instability1-3. It is usually seen in people after the age of 60, but there is a earlier onset form of PD seen under 40 years of age. This is often caused by genetic mutations that alter the pathways needed to protect neurons and is identified as Familial PD1,2. Of all PD in North America, 10% of diagnosis have been identified as Familial PD, and of those 70% have been found to have dysfunctional PINK1/ Parkin proteins3-5. The studies reviewed have shown that the PINK1/Parkin pathway is imperative in mitochondrial homeostasis – including mitophagy and biogenesis – and their dysfunction leads to cytotoxic conditions neuronal death2-8. Methods. PINK1 null mice model was utilized to observe the effects on mitochondria5. The accumulation of reactive oxygen species (ROS) and mitochondrial debris was analyzed with immunohistochemistry5. This was statistically correlated to the presence of Parkinsonian symptoms in the mice. In a separate study, S-nitrosylation was used as a method of silencing the PINK1 protein4. The level of PINK1 accumulation and mitochondrial dysfunction was measured using immunohistochemistry4. Results. PINK1 null mice were found to develop Parkinsonian symptoms of akinesia and tremors5. Their immunohistochemistry results showed an accumulation of mitochondrial debris, dysfunctional mitochondria, and high levels of ROS within the neurons5,7. They were also found to have lost more neurons than the control mice with intact PINK1 protein highlighting the role of PINK1 in being neuroprotective5,7. Additionally, they also had less mitochondrial biogenesis when compared to control mice that were put under oxidative stress5. The study that conducted S-nitrosylation of the PINK1 protein showed decreased mitophagy and mitochondrial biogenesis leading to an accumulation of cytotoxic factors4. Furthermore, the study found that the neurons that were lost could be localized to the SNPc4. Conclusion. Studies have found the association of PINK1 protein in Parkinson’s disease in both humans and in mice model which provides insight into possible therapeutic targets7,8. It also shows that when the mitophagic and mitochondrial biogenesis pathways of the cells are not functioning properly, a cytotoxic situation is created that leads to neuronal cell death. The neuroprotective effect of PINK1 protein is further highlighted in situations where S-nitrosylation of the protein leads to loss of neurons localized to the substantia nigra pars compacta5,7,8.
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- Lu W, Karuppagounder SS, Springer DA, et al. Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson’s-like movement disorder. Nat Commun. 2014;5:4930. Published 2014 Sep 15. doi:10.1038/ncomms5930
- Liu Y, Yan J, Sun C, et al. Ameliorating mitochondrial dysfunction restores carbon ion-induced cognitive deficits via co-activation of NRF2 and PINK1 signaling pathway. Redox Biol. 2018;17:143–157. doi:10.1016/j.redox.2018.04.012
- Oh CK, Sultan A, Platzer J, et al. S-Nitrosylation of PINK1 Attenuates PINK1/Parkin-Dependent Mitophagy in hiPSC-Based Parkinson’s Disease Models. Cell Rep. 2017;21(8):2171–2182. doi:10.1016/j.celrep.2017.10.068
- Park, SY, Choi, SE, Koh HC. PGAM5 regulates PINK1/Parkin-mediated mitophagy via DRP1 in CCCP-induced mitochondrial dysfunction. Toxicology. 2018; 284: 120-128. Published date 2017 Dec 11.
- Xu Y et. al. – Opioid Receptor Activation Attenuates Hypoxia/ MPP-Induced Downregulation of PINK1: a Novel Mechanism of Neuroprotection Against Parkinsonian Injury. Molecular Neurobiology. 2019; 56:252-266. doi:10.007/s12035-018-1043-7.
- Nardin A, Schrepfer E, Ziviani E. Counteracting PINK/Parkin Deficiency in the Activation of Mitophagy: A Potential Therapeutic Intervention for Parkinson’s Disease. Curr Neuropharmacol. 2016;14(3):250–259. doi:10.2174/1570159X13666151030104414
- Choong, CJ, Mochizuki, H. Gene therapy targeting mitochondrial pathway in Parkinson’s disease. J Neural Transm. 2017; 124: 193-207. doi:10.1007/s00702-016-1616-4