The impact of dysfunctional Parkin and PINK-1 on mitochondrial quality control in the pathogenesis of Parkinson’s Disease
Introduction. Parkinson’s Disease (PD) is a progressive, neurodegenerative disease of the basal ganglia that primarily affects movement initiation and motor control.1 A key pathological hallmark of PD is the death of dopaminergic neurons in the substantia nigra.1,2 This neuronal dysfunction has been linked to mitochondrial dysfunction due to the vital role that mitochondria play in establishing and maintaining neuronal health.3-5 As such, mitochondrial quality control (MQC) is a current research focus for neurodegenerative diseases, including PD.5 Furthermore, since both inherited PD-genes and environmental stressors are known to dysregulate mitochondrial function, MQC is a potential converging point for both the familial and sporadic cases of PD.6 Current research has focused on two main aspects of MQC, mitophagy and biogenesis, both of which require functional Parkin and PINK-1 proteins.3,5,7-9 By focusing on MQC pathways that bypass the need for functional Parkin and PINK-1, researchers are hopeful to develop new treatments for PD.5 Methods. Human SH-SY5Y neuroblastoma cells were transduced with shPINK1 or shControl lentivirus, then were further induced with OligomycinA/AntimycinA, to mimic the dysfunctionality of stressed cells in PINK-1 deficient subjects.10 The level of SQSTM1, a gene for autophagy, was compared between control cells and Trifluoperazine-treated cells, by using a qRT-PCR analysis of mRNA expression levels after 24 hours.10 Another study used adult knockout of Parkin in mouse ventral midbrains with shPARIS lentivirus and observed the changes in mitochondrial size, number, and structural patterns using TEM analysis.7,9 Follow-up studies used western blot analyses with a MAO-B oxidative stress induction model to observe the effects of adding exogenous PGC-1α to dopaminergic SNpc cells.11 Results. The first study showed that PINK-1 is required for adaptive responses to mitochondrial stress.10 However, they found that Trifluoperazine (TFP) could bypass the dysfunctional PINK-1 pathway and stimulate autophagy in stressed cells.10 Another study showed that PINK-1 and Parkin work together to inhibit PARIS, and consequently prevent PARIS’s repression of PGC-1α.7,9 Since PGC-1α is the master co-regulator of mitochondrial function and biogenesis, inhibiting its repression by PARIS is paramount to mitochondrial health.7,9 These studies showed that increased expression or restoration of PGC-1α pose potential therapies for patients with upregulated PARIS due to dysfunctional Parkin/PINK-1.7,11 Conclusions. Current research on neurodegenerative diseases has centered on mitochondrial quality control, specifically focusing on mitophagy and mitochondrial biogenesis. Potential therapies currently include mitophagy stimulation using TFP to bypass the dysfunctional PINK-1 pathway, and biogenesis stimulation through PGC-1α overexpression or PARIS inhibition.
- Miller, Diane B., and James P. O’Callaghan. “Biomarkers of Parkinson’s Disease: Present and Future.” Metabolism: clinical and experimental3 0 1 (2015): S40–S46.
- Rizek, Philippe, Niraj Kumar, and Mandar S. Jog. “An Update on the Diagnosis and Treatment of Parkinson Disease.” CMAJ : Canadian Medical Association Journal16 (2016): 1157–1165. PMC.
- Karabiyik C, Lee MJ, Rubinsztein DC. Autophagy impairment in Parkinson’s disease. Essays in Biochemistry. 2017;61:711-720.
- Whitworth AJ, Pallanck LJ. PINK1/Parkin mitophagy and neurodegeneration—what do we really know in vivo? Genetics & Development. 2017;44:47-53.
- Cieri D, Brini M, Cali T. Emerging (and converging) pathways in Parkinson’s disease: keeping mitochondrial wellness. Biochemical and biophysical research communications. 2017;483:1020-1030.
- Kaidery NA, Thomas B. Current perspective of mitochondrial biology in Parkinson’s disease. Neurochemistry International. 2018.
- Stevens DA, Lee Y, Kang HC, et al. Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(37):11696-11701.
- Yan MH, Wang X, Zhu X. Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free radical biology & medicine. 2013;62:90-101.
- Lee Y, Stevens DA, Kang S-U, Dawson V, Shin JH, Dawson TM. PINK1 primes parkin-mediated ubiquitination of PARIS in dopaminergic neuronal survival. Cell Reports. 2017;18(4):918-932.
- Zhang Y, Nguyen D, Olzomer E, Puvanendran A, Phillips B, Hesselson D. Rescue of pink1 deficiency by stress-dependent activation of autophagy. Cell Chemical Biology. 2017;24:471-480
- Siddiqui A, Rane A, Rajagopalan S, Chinta SJ, Anderson JK. Detrimental effects of oxidative losses in Parkin activity in a model of sporadic Parkinson’s disease are attenuated by restoration of PGC-1α. Neurobiology of Disease. 2016;93:115-120.