Jennifer Oruebor

 Introduction. Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by motor symptoms including tremor, bradykinesia, and postural imbalance. ¹ PD pathology includes loss of dopaminergic neurons in the substantia nigra pars compacta and the deposition of alpha-synuclein protein aggregates (Lewy bodies).¹ The loss of dopaminergic neurons in the substantia nigra pars compacta leads to loss of dopamine in the striatum–the primary mechanism leading to motor symptoms in PD.¹ Oxidative stress (OS) is an imbalance in the rate of production and removal of reactive oxygen species (ROS), and it has been found to play a central role in the degeneration of dopaminergic neurons.² The WNT/b-Catenin pathway has downstream target genes that decrease oxidative stress and promote cell survival. GSK-3b is the main inhibitor of this pathway by sequestering b-catenin and targeting it for degradation.³ GSK-3b inhibition can upregulate the WNT/b-Catenin pathway and modulate OS, making it a therapeutic option in PD. Methods. Researchers generated animal and cell line models of PD using either MPP+, 6-OHDA or rotenone. Prior to insult, researchers introduced a GSK-3b inhibitor, antioxidant or both. Behavioral tests were completed with mice and rat models to assess motor and cognitive function. Following testing, animals were sacrificed and brain tissue was analyzed by immunohistochemistry. Flow cytometry was done to measure ROS in tissue samples. Cell lines were assessed via immunofluorescent microscopy. Results. Wu et al. found that in vivo administration of Lithium, a GSK-3b inhibitor, in 6-OHDA treated rats improved behavioral deficits and dopaminergic neuron loss, increased antioxidant levels, inactivated GSK-3b, reduced MDA in the striatum and elevated b-catenin. ⁴ Ren et al. found that GSK-3b inactivation reduced MPTP-induced behavioral impairments, MPTP-induced Tyrosine Hydroxylase (TH) loss, and Dopaminergic neuron loss in mouse-model of PD. ⁵ Li et al. found that administration of tideglusib, a GSK-3b inhibitor, alleviated TH positive neuron loss in substantia nigra, increased number of Nissl positive neurons, and improved motor symptoms in MPTP mice-models of PD. ⁶ Zhang et al. found that GSK-3b inhibitors increased the level of b-catenin and attenuated the cell death due to rotenone in PC12 cells. If b-catenin was silenced with siRNA, these effects were not seen indicating the importance of b-catenin in the WNT signaling pathway for PC12 cell survival.⁷ Conclusion. These studies show that GSK-3b inhibition is neuroprotective by upregulating the WNT/b-Catenin pathway leading to decreased OS and reduced loss of dopaminergic neurons. There was also improvement of motor symptoms in animal models. This presents a novel therapeutic target to modulate neurodegeneration in PD.

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2. Guo J-D, Zhao X, Li Y, Li G-R, Liu X-L. Damage to dopaminergic neurons by oxidative stress in Parkinson’s disease (Review). Int J Mol Med. 2018;41(4):1817-1825. doi:10.3892/ijmm.2018.3406
3. Vallée A, Vallée J-N, Lecarpentier Y. Parkinson’s Disease: Potential Actions of Lithium by Targeting the WNT/β-Catenin Pathway, Oxidative Stress, Inflammation and Glutamatergic Pathway. Cells. 2021;10(2):230. doi:10.3390/cells10020230
4. Wu D-M, Han X-R, Wen X, et al. Salidroside Protection Against Oxidative Stress Injury Through the Wnt/β- Catenin Signaling Pathway in Rats with Parkinson’s Disease. Cell Physiol Biochem. 2018;46(5):1793- 1806. doi:10.1159/000489365
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7. Zhang L, Cen L, Qu S, et al. Enhancing Beta-Catenin Activity via GSK3beta Inhibition Protects PC12 Cells against Rotenone Toxicity through Nurr1 Induction. PLOS ONE. 2016;11(4):e0152931. doi:10.1371/journal.pone.0152931