In the context of AD-related pathology, afobazole, which is a pan-selective Sig1R-Sig2R ligand, reduces neurotoxic microglia stimulation and apoptosis induced by fragments of amyloid beta (Aβ) (Behensky et al. 2015), exerts neurogenic and neuroprotective effects in neural progenitor cells derived from adult rat brain (Liu et al. For example, progesterone, which binds to both Sig2R and PGRMC1 (Chu et al. Moreover, Sig2R/PGRMC1 signaling has been implicated in cellular processes relevant to CNS diseases, including neuroprotection, axonal migration, and mitochondrial protection (Cahill 2007 Qin et al. Within the CNS, Sig2R/PGRMC1 is highly expressed in the cortex and hippocampus, two regions known to be important for cognitive function (French and Pavlidis 2011 Izzo et al. We became interested in Sig2R/PGRMC1 several years ago as a possible target for drug discovery in neurodegenerative diseases because of its widespread occurrence in the CNS and its putative involvement in calcium homeostasis. Notwithstanding this controversy, we originally identified the compounds described herein as Sig2R ligands and found they modulate a PGRMC1-related pathway thus, we will refer to the biological target by the descriptor Sig2R/PGRMC1. These two observations are not necessarily mutually exclusive, and further work is needed to clarify the identity and function of the Sig2R. Several reports conclude PGRMC1 and Sig2R are distinct molecular entities (Abate et al. 2016) and is involved in neuroprotection and axonal migration (Runko and Kaprielian 2004 Cahill 2007 Rohe et al.
PGRMC1 is a cytochrome-like single-transmembrane protein that has been structurally characterized as a heme-bound dimer (Kabe et al. Recent photoaffinity and fluorescent probe experiments suggest that the putative Sig2R binding site is in the progesterone receptor membrane component-1(PGRMC1) protein complex (Xu et al. Although Sig2Rs have not been cloned, they are widely distributed in the CNS and are implicated in cellular processes relevant to cancer and CNS disorders (Bowen 2000 Mach et al. 2010, 2016 Hashimoto 2013) the structure of a trimer of Sig1R has been characterized by X-ray crystallography (Schmidt et al. Sig1Rs, which have been cloned, are chaperone proteins that reside in the endoplasmic reticulum–mitochondrion interface as well as in nuclear and plasma membranes (Su et al.
Both sigma receptor subtypes are expressed in the central nervous system (CNS) and distinguished from one another based upon their affinity for different ligands and biological profiles. 2014a), has only recently been explored as a possible strategy for treating neurological disorders. It is notable that modulating sigma receptors, for which the two known subtypes are sigma 1 (Sig1R) and sigma 2 (Sig2R) (Matsumoto et al. 2014), and there remains an unmet need for therapeutic approaches to treat AD. However, these medications do not alter pathology underlying the disease (Cummings et al. Current therapies for AD rely upon transiently mitigating some of its symptoms. The multifaceted pathology of AD makes it difficult to develop effective treatments.
The hallmarks of AD include neuronal loss, neuroinflammation, and the accumulation of amyloid plaques and neurofibrillary tangles (Mattson 2004 Citron 2010 Huang and Mucke 2012). progesterone receptor membrane component-1Īlzheimer's disease (AD) is currently the sixth leading cause of death in the US (James et al.These results demonstrate that Sig2R is a promising therapeutic target for neurocognitive disorders including AD. Last, we demonstrate that SAS-0132 improves cognitive performance both in the Thy-1 hAPP L ond/Swe+ transgenic mouse model of AD and in healthy wild-type mice. Since this neuroprotective effect is replicated by genetic knockdown and knockout of vem-1, the ortholog of progesterone receptor membrane component-1 (PGRMC1), these results suggest that Sig2R ligands modulate a PGRMC1-related pathway. The Sig2R ligands SAS-0132 and JVW-1009 are neuroprotective in a C. elegans model of amyloid precursor protein-mediated neurodegeneration. We report that SAS-0132 and DKR-1051, selective ligands of Sig2R, modulate intracellular Ca 2+ levels in human SK-N-SH neuroblastoma cells. Herein, we report the identification of a novel class of Sig2R ligands and their cellular and in vivo activity in experimental models of Alzheimer's disease (AD). Accumulating evidence suggests that modulating the sigma 2 receptor (Sig2R) can provide beneficial effects for neurodegenerative diseases.
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