Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases

Abstract

There is a large unmet medical need to develop disease-modifying treatment options for individuals with age-related degenerative diseases of the central nervous system. The sigma-2 receptor (S2R), encoded by TMEM97, is expressed in brain and retinal cells, and regulates cell functions via its co-receptor progesterone receptor membrane component 1 (PGRMC1), and through other protein–protein interactions. Studies describing functions of S2R involve the manipulation of expression or pharmacological modulation using exogenous small-molecule ligands. These studies demonstrate that S2R modulates key pathways involved in age-related diseases including autophagy, trafficking, oxidative stress, and amyloid-β and α-synuclein toxicity. Furthermore, S2R modulation can ameliorate functional deficits in cell-based and animal models of disease. This review summarizes the current evidence-based understanding of S2R biology and function, and its potential as a therapeutic target for age-related degenerative diseases of the central nervous system, including Alzheimer’s disease, α-synucleinopathies, and dry age-related macular degeneration.

The Sigma Receptors in Alzheimer’s Disease: New Potential Targets for Diagnosis and Therapy

“…The knockout of the TMEM97/σ 2 receptor, or PGRMC-1, or both, as well as inhibition of the TMEM97/σ 2 receptor were all shown to reduce the uptake of Aβ 1-42 and ApoE in primary neurons [44]. Moreover, the expression of the σ 2 receptor is dramatically increased by approximately 1.5-fold in AD [165], and is localized to an increased area of synapses (approximately 1.8-fold) in brain tissue taken from people suffering from AD compared with healthy controls, suggesting a compensatory response to AD-related synaptic depression [148,165]. Neurons with knockout of the PGRMC-1 protein also displayed reduced capacity in binding to AβO [160].…”

“…It functions as a housekeeping protein under normal settings [146]. The σ 2 receptor/TMEM97, a member of the expanded emopamil binding protein (EPR) superfamily, has sterol isomerase activity [147,148] and plays a critical role in cholesterol biology, with correlated expression genes taking part in lipid metabolism [147]. High expression of the σ 2 receptor was found in a variety of tumor cells, with nearly 10-fold higher expression in a proliferating state tumor compared to a quiescent state [149][150][151][152].…”

“…Further, results from recent studies have indicated the critical involvement of the σ 2 receptor in the pathophysiology of many brain disorders. Thus, the σ 2 receptor has been proposed as a novel therapeutic target for AD, HD, PD [147,154,155], depression [156], schizophrenia [157], neuropathic pain [158,159], and age-related macular degeneration [148].…”

“…The loss or pharmacological inhibition of one or both of these proteins results in the disruption of the complex leading to decreased uptake of AβO and ApoE in neurons. Targeting the σ 2 receptor/TMEM97 represents a new strategy for inhibiting Aβ neurotoxicity and slowing neurodegeneration in AD [53,148].…”

Discovery of WLB-89462, a New Drug-like and Highly Selective σ2 Receptor Ligand with Neuroprotective Properties

“…The potential signal transduction of the σ 2 R is not yet completely understood, but it seems to modulate calcium and potassium channels and to interact with caspases, epidermal growth factor receptor (EGFR), and mammalian target of rapamycin (mTOR) signaling pathways . As in the case of the σ 1 R, it is also involved in dopaminergic transmission, microglia activation, and neuroprotection . It plays a key role in amyloid β (Aβ)-induced synaptotoxicity, and σ 2 R ligands have been shown to be neuroprotective by blocking the interaction of Aβ oligomers with the σ 2 R and to improve cognitive performance in a transgenic mouse model of Alzheimer’s disease (AD) .…”