Retinal Photoreceptor Protection in an AMD-Related Mouse Model by Selective Sigma-1 or Sigma-2 Receptor Modulation.

The structurally and genetically distinct sigma-1 receptor (S1R) and sigma-2 receptor (S2R) comprise a unique class of drug binding sites. Their alleles are associated with human diseases involving neuronal systems, such as age-related macular degeneration (AMD) characterized by photoreceptor and retinal pigment epithelium (RPE) atrophy. Previous studies have suggested neuroprotective benefits for the brain and retina from pharmacological modulation of S1R and/or S2R.

Decreased outflow facility and Schlemm's canal defects in a mouse model of glaucoma.

Previously we identified B6.EDA mice as a novel mouse model that presents with elevated IOP and trabecular meshwork damage. Here, we expand on our previous findings by measuring aqueous humor outflow facility and analyzing the integrity of the inner wall of Schlemm's canal.

Fibronectin extra domain A (FN-EDA) causes glaucomatous trabecular meshwork, retina, and optic nerve damage in mice.

Background: Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of primary open angle glaucoma and is due to trabecular meshwork (TM) damage. Here, we investigate the role of an endogenous Toll-like receptor 4 (TLR4) ligand, FN-EDA, in the development of glaucoma utilizing a transgenic mouse strain (B6.EDA) that constitutively expresses only FN containing the EDA isoform.

TLR4 signaling modulates extracellular matrix production in the lamina cribrosa.

The optic nerve head (ONH) is a place of vulnerability during glaucoma progression due to increased intraocular pressure damaging the retinal ganglion cell axons. The molecular signaling pathways involved in generating glaucomatous ONH damage has not been fully elucidated. There is a great deal of evidence that pro-fibrotic TGFβ2 signaling is involved in modulating the ECM environment within the lamina cribrosa (LC) region of the ONH.

TMEM97 ablation aggravates oxidant-induced retinal degeneration.

The retinal pigment epithelium (RPE) is critical to the survival of the overlying photoreceptors. Subject to light exposure and active metabolism, the RPE and photoreceptors are particularly susceptible to oxidative damage that plays an important part in age-related macular degeneration (AMD). Recent meta-analyses identified TMEM97 as a new putative AMD risk locus, though it is yet to be functionally verified.

Fibronectin extra domain A (FN-EDA) elevates intraocular pressure through Toll-like receptor 4 signaling.

Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of primary open angle glaucoma and is due to trabecular meshwork (TM) damage, which leads to impaired aqueous humor outflow. Here, we explore a novel molecular mechanism involved in glaucomatous TM damage. We investigated the role of an endogenous Toll-like receptor 4 (TLR4) ligand, fibronectin-EDA (FN-EDA), in TGFβ2-induced ocular hypertension in mice.

Role of the sigma-1 receptor chaperone in rod and cone photoreceptor degenerations in a mouse model of retinitis pigmentosa.

Background: Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease yet with no effective treatment available. The sigma-1 receptor (S1R), a ligand-regulated chaperone, emerges as a potential retina-protective therapeutic target. In particular, pharmacological activation of S1R was recently shown to rescue cones in the rd10 mouse, a rod Pde6b mutant that recapitulates the RP pathology of autonomous rod degeneration followed by secondary death of cones.

APEX2-enhanced electron microscopy distinguishes sigma-1 receptor localization in the nucleoplasmic reticulum.

The sigma-1 receptor (Sig1R) is an endoplasmic reticulum chaperonin that is attracting tremendous interest as a potential anti-neurodegenerative target. While this membrane protein is known to reside in the inner nuclear envelope (NE) and influences transcription, apparent Sig1R presence in the nucleoplasm is often observed, seemingly contradicting its NE localization. We addressed this confounding issue by applying an antibody-free approach of electron microscopy (EM) to define Sig1R nuclear localization.

Peeking into Sigma-1 Receptor Functions Through the Retina.

This review discusses recent advances towards understanding the sigma-1 receptor (S1R) as an endogenous neuro-protective mechanism in the retina , a favorable experimental model system. The exquisite architecture of the mammalian retina features layered and intricately wired neurons supported by non-neuronal cells. Ganglion neurons, photoreceptors , as well as the retinal pigment epithelium, are susceptible to degeneration that leads to major retinal diseases such as glaucoma , diabetic retinopathy , and age-related macular degeneration (AMD), and ultimately, blindness.

The Sigma-1 Receptor-A Therapeutic Target for the Treatment of ALS?

The membrane bound 223 amino acid Sigma-1 Receptor (S1R) serves as a molecular chaperone and functional regulator of many signaling proteins. Spinal cord motor neuron activation occurs, in part, via large ventral horn cholinergic synapses called C-boutons/C-terminals. Chronic excitation of motor neurons and alterations in C-terminals has been associated with Amyotrophic Lateral Sclerosis (ALS ).

An intraocular drug delivery system using targeted nanocarriers attenuates retinal ganglion cell degeneration.

Glaucoma is a common blinding disease characterized by loss of retinal ganglion cells (RGCs). To date, there is no clinically available treatment directly targeting RGCs. We aim to develop an RGC-targeted intraocular drug delivery system using unimolecular micelle nanoparticles (unimNPs) to prevent RGC loss.

Sigma-1 receptor expression in the dorsal root ganglion: Reexamination using a highly specific antibody.

Sigma-1 receptor (S1R) is a unique pluripotent modulator of living systems and has been reported to be associated with a number of neurological diseases including pathological pain. Intrathecal administration of S1R antagonists attenuates the pain behavior of rodents in both inflammatory and neuropathic pain models. However, the S1R localization in the spinal cord shows a selective ventral horn motor neuron distribution, suggesting the high likelihood of S1R in the dorsal root ganglion (DRG) mediating the pain relief by intrathecally administered drugs.

The Sigma-2 Receptor and Progesterone Receptor Membrane Component 1 are Different Binding Sites Derived From Independent Genes.

The sigma-2 receptor (S2R) is a potential therapeutic target for cancer and neuronal diseases. However, the identity of the S2R has remained a matter of debate. Historically, the S2R has been defined as (1) a binding site with high affinity to 1,3-di-o-tolylguanidine (DTG) and haloperidol but not to the selective sigma-1 receptor ligand (+)-pentazocine, and (2) a protein of 18-21 kDa, as shown by specific photolabeling with [(3)H]-Azido-DTG and [(125)I]-iodoazido-fenpropimorph ([(125)I]-IAF).

Subcellular localization of the sigma-1 receptor in retinal neurons - an electron microscopy study.

The Sigma-1 receptor (S1R) is known to play a protective role in the central nervous system including the retina. A major barrier for understanding the underlying mechanism is an ambiguity of S1R subcellular localizations. We thus conducted the first electron microscopy (EM) study of S1R subcellular distribution in the mouse retina.

Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type a.

Botulinum neurotoxin type A (BoNT/A) is a highly potent neurotoxin that elicits flaccid paralysis by enzymatic cleavage of the exocytic machinery component SNAP25 in motor nerve terminals. However, recent evidence suggests that the neurotoxic activity of BoNT/A is not restricted to the periphery, but also reaches the CNS after retrograde axonal transport. Because BoNT/A is internalized in recycling synaptic vesicles, it is unclear which compartment facilitates this transport.

Role of the Sigma-1 receptor in Amyotrophic Lateral Sclerosis (ALS).

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease affecting spinal cord motoneurons (MN) with an associative connection to Frontotemporal Lobar Dementia (FTLD). The endoplasmic reticulum (ER) bound Sigma-1 Receptor (S1R) chaperone protein localizes to specialized ER cisternae within 10 nm of the plasma membrane in spinal cord ventral horn cholinergic post synaptic C-terminals. Removal of the S1R gene in the Superoxide Dismutase-1 (SOD-1) mouse model of ALS exacerbated the neurodegenerative condition and resulted in a significantly reduced longevity when compared to the SOD-1/S1R wild type (WT) mouse.

Development of benzophenone-alkyne bifunctional sigma receptor ligands.

Sigma (σ) receptors are unique non-opioid binding sites that are associated with a broad range of disease states. Sigma-2 receptors provide a promising target for diagnostic imaging and pharmacological interventions to curb tumor progression. Most recently, the progesterone receptor (PGRMC1, 25 kDa) has been shown to have σ2 receptor-like binding properties, thus highlighting the need to understand the biological function of an 18 kDa protein that exhibits σ2-like photoaffinity labeling (denoted here as σ2-18k) but the amino acid sequence of which is not known.

Accelerated retinal ganglion cell death in mice deficient in the Sigma-1 receptor.

Purpose: The sigma-1 receptor (σR1), a ligand-operated chaperone, has been inferred to be neuroprotective in previous studies using σR1 ligands. The σR1 specificity of the protective function, however, has yet to be firmly established, due to the existence of non-σR1 targets of the ligands. Here, we used the σR1-knockout mouse (Sigmar1(-/-)) to demonstrate unambiguously the role of the σR1 in protecting the retinal ganglion cells against degeneration after acute damage to the optic nerve.

In vitro interaction of tubulin with the photoreceptor cGMP phosphodiesterase gamma-subunit.

The alpha and beta tubulins compose the microtubule cytoskeleton which is involved in many cellular processes such as vesicular transport. The photoreceptor cells in the retina are neurons specialized for phototransduction. Here we report a novel interaction between tubulin and the photoreceptor cGMP phosphodiesterase (PDE6) gamma subunit (PDE gamma).

The sigma1 receptor interacts with N-alkyl amines and endogenous sphingolipids.

The sigma1 receptor is distinguished for its ability to bind various pharmacological agents including drugs of abuse such as cocaine and methamphetamine. Some endogenous ligands have been identified as putative sigma1 receptor regulators. High affinity ligands for the sigma1 receptor contain a nitrogen atom connected to long alkyl chains.

Ligand-dependent localization and intracellular stability of sigma-1 receptors in CHO-K1 cells.

Background: Sigma-1 receptors are involved in regulation of neuronal activities presumably through regulation of the activity of ion channels. Sigma-1 receptors also play a role in growth and metastasis of cancerous cells. Intracellular distribution of sigma-1 receptors have been linked to sphingolipid-enriched domains.

Identification of RanBP2- and kinesin-mediated transport pathways with restricted neuronal and subcellular localization.

Ran-binding proteins, karyopherins, and RanGTPase mediate and impart directionality to nucleocytoplasmic transport processes. This biological process remains elusive in neurons. RanBP2 has been localized at the nuclear pore complexes and is very abundant in the neuroretina.

Species-specific subcellular localization of RPGR and RPGRIP isoforms: implications for the phenotypic variability of congenital retinopathies among species.

The retinitis pigmentosa GTPase regulator (RPGR) is encoded by the X-linked RP3 locus, which upon genetic lesions leads to neurodegeneration of photoreceptors and blindness. The findings that RPGR specifically and directly interacts in vivo and in vitro with retina-specific RPGR-interacting protein 1 (RPGRIP) and that human mutations in RPGR uncouple its interaction with RPGRIP provided the first clue for the retina-specific pathogenesis of X-linked RP3. Recently, mutations in RPGRIP were found to lead to the retinal dystrophy, Leber congenital amaurosis.