The Role of LRRK2 Mutations in Parkinson’s Disease Pathogenesis
Introduction. Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra, decreasing dopamine production and affected striatal function in the basal ganglia7. Without dopamine, there is an inhibitory signal to the thalamus and decreased excitation of the motor and premotor cortices. This results in both motor and non-motor symptoms, including bradykinesia, resting tremor, stooped posture, rigidity, autonomic disorders, sleep disturbances, depression, and dementia2,7. While PD affects approximately 10 million people worldwide, the etiology of PD is not yet completely understood and treatment is currently limited to temporarily slowing the progression3. Current studies do show that gene mutations in LRRK2, Parkin, and PINK1 have been associated with rare familial forms and LRRK2 has also been associated with sporadic forms5,7. How can further understanding of LRRK2 mutations in PD pathogenesis promote improved PD treatment? Methods. Gene expression profiles were obtained of mice with wild-type LRRK2, that were knock-out LRRK2 and that had the LRRK2(R1441G) mutation. Luminescence assays were done to determine cell death and oxidative stress. Immunohistochemistry of mouse neuronal stem cells (NSCs) was done to look for markers of differentiation (e.g. Nestin). RNA isolation, cDNA production, and RT-qPCR were used to study miRNA (let-7a). Results. A mutation in LRRK2 alters the regulation of miRNA as seen by the down-regulation of let-7a1. The mice with the LRRK2(R1441G) mutation show a 50% decrease in differentiation1. In support of these findings, NSCs with the R1441G mutation show increased cell death after induction of differentiation and strongly elevated reactive oxygen species1,6. Conclusion. Studies have found that the down-regulation of let-7a can be detected in plasma levels and that this detection has high sensitivity and specificity to detect PD2. Earlier detection allows for earlier treatment. Additionally, once LRRK2 mutations are corrected in the induced pluripotent stem cells (iPSCs) derived from PD patients (e.g. via CRISP/CAS9 gene editing technology), iPSC-derived dopaminergic progenitors could be transplanted back to the PD patients1,3,4. This could provide improved, more long-term treatment.
- Bahnassawy, Lamiaa, et al. The Parkinsons Disease-Associated LRRK2 Mutation R1441G Inhibits Neuronal Differentiation of Neural Stem Cells. Stem Cells and Development, vol. 22, no. 18, 2013, pp. 2487–2496., doi:10.1089/scd.2013.0163
- Chen L, Yang J, Lü J, Cao S, Zhao Q, Yu Z. Identification of aberrant circulating miRNAs in Parkinson’s disease plasma samples. Brain Behav. 2018;8(4):e00941. doi:10.1002/brb3.941.
- Han F, Wang W, Chen B et al. Human induced pluripotent stem cell–derived neurons improve motor asymmetry in a 6-hydroxydopamine–induced rat model of Parkinson’s disease. Cytotherapy. 2015;17(5):665-679. doi:10.1016/j.jcyt.2015.02.001.
- Liu H, Ho P, Leung G et al. Combined LRRK2 mutation, aging and chronic low dose oral rotenone as a model of Parkinson’s disease. Sci Rep. 2017;7:40887. doi:10.1038/srep40887.
- Puschmann, Andreas. New Genes Causing Hereditary Parkinson’s Disease or Parkinsonism. Current Neurology and Neuroscience Reports, vol. 17, no. 9, 2017, p. 66., doi:10.1007/s11910-017-0780-8.
- Sanders L, Laganière J, Cooper O et al. LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson’s disease patients: Reversal by gene correction. Neurobiol Dis. 2014;62:381-386. doi:10.1016/j.nbd.2013.10.013.
- Shen, Yan, et al. The Implication of Neuronimmunoendocrine (NIE) Modulatory Network in the Pathophysiologic Process of Parkinson’s Disease. Cellular and Molecular Life Sciences, vol. 74, no. 20, 2017, pp. 3741–3768., doi:10.1007/s00018-017-2549-2.