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.

Keywords: Alzheimer’s disease (AD); Huntington’s disease; MAC30; Niemann–Pick disease type C (NPC); PGRMC1; Parkinson’s disease (PD); S2R; TMEM97; degenerative disease; dementia with Lewy bodies (DLB); dry age-related macular degeneration (dry AMD); prion protein, PrPC; schizophrenia; α-synuclein; σ2R.

Figure 2

S2R pharmacology and the overlap with TMEM97 and PGRMC1 biology. Two putative endogenous ligands for S2R have been identified, although additional studies are needed to elucidate their roles under physiological and pathophysiological contexts. Despite this, several synthetic S2R ligands have been developed and used to investigate S2R function. Direct protein–protein interactions and functions of TMEM97 remain to be fully characterized; however, TMEM97 interacts directly with Niemann–Pick protein C1, as well as PGRMC1 and LDLR. PGRMC1 is more well-identified as a hormone receptor with multiple functions, including regulation of signal transduction pathways, protein–protein interactions, membrane trafficking, and autophagy. While ongoing studies attempt to elucidate the functions of each protein, S2R, TMEM97, and PGRMC1 converge in co-localization/co-expression and their regulation of amyloid-β binding. References: (1) [80,81]; (2) [82]; (3) [5,63,67,73,83,84,85,86,87,88,89,90]; (4) [62,66]; (5) [51,91,92]; (6) [16,61]; (7) [61,93,94]; (8) [1,59,95]; (9) [2,3,96]; (10) [97,98,99]; (11) [100]; (12) [78]; (13) [101,102]; (14) [103,104,105,106] Abbreviations: Aβ, amyloid-β; Apo-E, apolipoprotein-E; BDNF, brain-derived neurotrophic factor; DTG, di-o-tolylguanidine; EGFR, epidermal growth factor receptor; GLP-1R, glucagon-like peptide-1 receptor; Insig/Scap, insulin-induced gene/sterol regulatory element-binding protein cleavage-activating protein; LDLR, low-density lipoprotein receptor; MAP1LC3/UVRAG, microtubule-associated proteins 1A/1B light chain 3/UV radiation resistance associated gene protein; mPRα, membrane progesterone receptor alpha; NPC1, Niemann–Pick protein C1; PAIRBP, plasminogen activator inhibitor 1 mRNA-binding protein; PGRMC1, progesterone receptor membrane component 1; S2R, sigma-2 receptor; TMEM97, transmembrane protein 97; UNC/DCC, UNC-40/Deleted in Colorectal Cancer.

Figure 1

Timeline of the discovery and elucidation of S2R from inception to therapeutic modulation. References: Martin et al., 1976 [57]; Hanner et al., 1996 [58]; Xu et al., 2011 [59], Izzo et al., 2014 [2]; Sanchez-Pulido & Ponting, 2014 [60]; Alon et al., 2017 [61]; Riad et al., 2020 [62]; Alon et al., 2021 [63]; Izzo et al., 2021 [64]; Limegrover et al., 2021 [4]; Colom-Cadena et al., 2021 [65]. Abbreviations: AD, Alzheimer’s disease; Aβ, amyloid-β; LDL, low-density lipoprotein; PD, Parkinson’s disease; PGRMC1, progesterone receptor membrane component 1; S1R, sigma-1 receptor; S2R, sigma-2 receptor; TMEM97, transmembrane protein 97.

Figure 3

Structure–function of S2R and role of S2R small molecule modulators in restoring cell health and function. The amyloid-β oligomer receptor is a protein complex (light blue) that binds amyloid-β oligomers and is comprised of cellular prion protein (PrP^c) along with other proteins including leukocyte immunoglobulin-like receptor subfamily B2/paired immunoglobulin-like type 2 receptor B (LilrB2), and possibly also Nogo-66 receptor 1 (Nogo). S2R small molecule modulator (green) binds to the S2R (TMEM97; purple). Abbreviations: AMD, age-related macular degeneration; Aβ, amyloid-β; PGRMC1, progesterone receptor membrane component 1; RPE, retinal pigment epithelium; S2R, sigma-2 receptor; TMEM97, transmembrane protein 97.

Figure 4

S2R modulator CT1812 slows the loss of synapses that is triggered by amyloid-β oligomers in vitro. High-resolution images of primary neuronal cell cultures exposed to β-amyloid oligomer are shown before the addition of CT1812 (left) and after the addition of CT1812 (right). Amyloid-β oligomers (red) bind to synaptic receptors and reduce numbers of synapses (Drebrin, green). The addition of CT1812 displaces amyloid-β oligomer binding and appears to block the effects induced by the amyloid-β oligomers, with the synapse numbers remaining at levels similar to control cultures. Reprinted with permission from Ref. [64], 2021, Izzo, et al.

Figure 5

S2R modulator CT1812 restores functional capabilities in a mouse model of Alzheimer’s disease. Transgenic mice exhibiting phenotypes associated with Alzheimer’s disease (red bars) performed significantly worse in both the fear trigger recall test and Morris water (MW) maze tests when compared with normal, non-transgenic mice (blue bars). After administration of CT1812, however, the Alzheimer model mice (green bars) performed similar to that of wild-type mice. These results are illustrative of the restorative effects of CT1812 on synaptic proteins and the animal’s functional capabilities. Adapted from Ref. [64], 2021, Izzo, et al.

Figure 6

Completed and ongoing or planned clinical trials with the S2R modulator CT1812 in Alzheimer’s disease, dementia with Lewy bodies (DLB), and dry AMD patients.

Figure 7

S2R modulators block the effects of α-synuclein oligomer binding to neurons. Representative microscopy images of primary neuronal cell cultures exposed to α-synuclein oligomer are shown with vehicle treatment (left) or after the addition of an S2R modulator (right). α-Synuclein oligomers (red) bind to neuronal processes (MAP2, green). The addition of an S2R modulator decreases the levels of α-synuclein oligomers bound to neurons [4].

Figure 8

S2R modulators reverse the effects of α-synuclein oligomers on lysosomal-associated membrane protein 2A expression and trafficking. (a) Microscopy images of a cell culture exposed to α-synuclein oligomer with or without S2R modulators and stained for lysosomal-associated membrane protein 2A (LAMP2A) were quantified. (** p < 0.01, ANOVA with Dunnett’s test for multiple comparisons; n.s., not significantly different compared with vehicle-treated cells.) (b) Cultures treated with increasing concentrations of α-synuclein oligomer (α-synO) exhibit membrane trafficking deficits. (c) These trafficking deficits are blocked by treatment with S2R modulators. Adapted from Ref. [4], 2021, Limegrover, et al.