In addition, the Sig-1R agonist PRE-084 can alleviate the pathological and behavioral defects in experimental models of Parkinson’s disease (PD) and ALS via upregulating neurotrophic factors or restoring Sig-1R’s functions.
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In animal models, Sig-1R KO mice exhibit the phenotypes of motor neuron degeneration, reduced ER-mitochondrial contacts, and perturbation of mitochondrial and calcium homeostasis depletion of Sig-1R in the SOD1 ∗G93A or SOD1 ∗G85R mouse also accelerates ALS progression and is accompanied by MAM disruption. Namely, mutations of the Sig-1R were found in amyotrophic lateral sclerosis (ALS) cohorts, and reduced density of Sig-1Rs was observed in the cerebral and cerebellar regions of the brain in early Alzheimer’s disease (AD) patients. Sig-1Rs have been linked to certain patients with neurological disorders. These phenomena are closely related to the stress conditions that characterize certain neurodegenerative diseases. Silencing of Sig-1Rs in primary neurons resulted in decreased mitochondrial membrane potential and aberrant formation of mitochondrial aggregates, reduced spine formation, enhanced superoxide productions, hampered axonal extension, reduced axonal density, and induced accumulation of phosphorylated tau and phosphorylated neurofilaments. Several lines of evidence support the hypothesis that the Sig-1R plays an important role in neuroprotection. The Sig-1R exists abundantly both in neurons and glia, implying that Sig-1Rs are involved in multiple physiological and pathological processes. In addition, Sig-1Rs function in lipid transport and regulations, autophagy, and inflammatory responses. Sig-1R antagonists also show combined effects against cancers through ER stress and reactive oxygen species (ROS) as well as the induction of the apoptotic pathways. Sig-1Rs are expressed higher in cancer tissues and correlated to decreased patient survival by influencing Ca 2 + homeostasis and are participating in the apoptosis-induced caspase activation. The Sig-1R plays promising roles not only in neuroprotection but also against other diseases. The Sig-1R can translocate to the plasma membrane proximity upon ligand stimulation, modulates cyclin-dependent kinase 5 (cdk5) activity via lipid modifications, or translocates to the nuclear membrane to regulate gene transcription. Sig-1Rs support cellular survival by maintaining mitochondrial homeostasis, Ca 2+ concentrations, and ER stress responses. Upon stress induction or ligand stimulation, the Sig-1R disassociates from BiP and translocates to other cellular compartments to regulate ion channels or other receptor activities, such as inositol 1,4,5-trisphosphate type 3 (IP3) receptor activity. As a chaperone protein, the Sig-1R interacts with ion channels, receptors, and lipids and is noted for its interaction with another ubiquitously expressed chaperone, BiP (also known as GRP78), during the resting state. Enriched in the mitochondrion-associated ER membrane (MAM) domain where there are ample cholesterol and lipids, the Sig-1R has been implicated in many neurodegenerative and psychiatric diseases, as well as in drug-abuse-regulated synaptic plasticity. Sigma-1 receptor (Sig-1R) is a transmembrane chaperone protein that resides in the endoplasmic reticulum (ER). Our study identifies the critical roles of Sig-1R in CNS homeostasis and supports the idea that functional complementation pathways are triggered in the Sig-1R KO pathology. Mutation or deficiency of Sig-1Rs has been observed in neurodegenerative models. We found that Nrf2 (nuclear factor erythroid 2-related factor 2), which functions to overcome the stress condition, was enhanced in the Sig-1R KO systems especially when cells were under stressful conditions. Upon proteasome or autophagy inhibitor treatments, the pronounced ubiquitinated proteins were further increased in Sig-1R KO neurons, indicating that the Sig-1R regulates both protein degradation and quality control systems. Astrogliosis was also observed in the neuron-glia culture. Our results showed that Sig-1R KO induces increased glial fibrillary acidic protein (GFAP) expression in primary neuron-glia cultures and in the whole brain of fetus mice with concomitantly increased accumulations of ubiquitinated proteins.
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Here, we used Sig-1R KO mice to examine brain expression profiles of astrocytes and ubiquitinated proteins, which are both hallmarks of central nervous system (CNS) pathologies. Sigma-1 receptor (Sig-1R) functions as a chaperon that interacts with multiple proteins and lipids and is implicated in neurodegenerative and psychiatric diseases.