Gor Kikanian

Background:  Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor symptoms such as tremors, rigidity, and bradykinesia. The Sigma-1 receptor (Sig-1R) is a unique transmembrane protein located in the endoplasmic reticulum that is involved in various cellular processes, including dopamine neurotransmission, calcium signaling, protein folding, and mitochondrial function. Recent studies have implicated the Sig-1R in the pathogenesis of PD, suggesting that targeting this receptor could be a potential therapeutic strategy for the disease.

Objectives:  This review aims to investigate the importance, function, and potential use of the Sigma-1 receptor as a therapeutic drug in Parkinson’s disease.

Search Methods:  PubMed was searched for relevant articles published between 2017-2023 using the following keywords: Parkinson’s disease, Sigma-1 receptor, dopamine, neuroprotection, and mitophagy.

Results:  Results: Sigma-1 receptor (σ1R) has emerged as a promising target in the pathogenesis and treatment of Parkinson’s disease (PD). In early-stage PD, σ1R has been found to be downregulated in the midbrain and striatum, areas reliant on dopamine for neurotransmission. Upon ligand stimulation or Ca2+ increases, σ1R translocates to the plasma membrane and interacts with DAT, a dopamine transporter. Recent studies using confocal and total internal reflection microscopy confirmed this process. Activating σ1R with agonist PRE-084 prevented methamphetamine-stimulated dopamine release from artificial CSF by approximately 50% and reduced intracellular Ca2+. PRE-084 also protected neuroblastoma cells from MPTP, inhibited loss of dopaminergic neurons, and restored motor abilities of PD-induced mice. Sigma-1 receptors also play a role in mitophagy of dopaminergic neurons, a process important for cell function and survival. In MPTP-induced mice models of PD, key mitophagy proteins, showed significantly decreased expression. Using LysoTracker Red dye, decreased lysosome counts were seen in the SNc of MPTP-induced mice, suggesting that lysosomal dysfunction could play a role in the development of PD. Sigma-1 receptor knockdown in dopaminergic cells resulted in defective clearance of depolarized mitochondria, and in WT dopaminergic cells, σ1R was shown to regulate mitophagy through the PINK1/Parkin pathway. Sigma-1 receptors are also involved in α-synuclein aggregation and phosphorylation in PD. Knockout of immunostained σ1R in mice models significantly increased the number of α-synuclein oligomers, although monomer levels were unchanged compared to WT mice. Pridopidine, a potential σ1R-mediated therapy for PD, has shown promise in preclinical trials by improving motor symptoms, and increasing brain dopamine release in animal models by up to 55%. Further clinical trials are needed to determine the efficacy and safety of pridopidine in PD patients.

Conclusion:  Studies have shown that Sigma-1 receptor plays a crucial role in the pathogenesis of Parkinson’s disease, particularly in the regulation of dopamine neurotransmission, mitophagy of dopaminergic neurons, and α-synuclein aggregation and phosphorylation. These findings suggest that targeting the Sigma-1 receptor may offer a promising therapeutic strategy for Parkinson’s disease. Pridopidine, a potential Sigma-1 receptor mediated therapy, shows potential as a treatment option for Parkinson’s disease. Further research is needed to fully understand the mechanisms underlying the Sigma-1 receptor’s involvement in Parkinson’s disease and to determine the full potential of Sigma-1 receptor targeted therapies for the treatment of this debilitating disease.

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