Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration

Wang, Jing; Saul, Alan; Roon, Penny; Smith, Sylvia B.

doi:10.1073/pnas.1521749113

Cited by 69 publications

(125 citation statements)

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“…SIGMAR1 modulates a variety of signaling pathways including ion channels, GPCRs, lipid rafts, ER stress response [14,15], as well as chromatin remodeling [16]. Studies including our own [17,18] support a protective role of SIGMAR1 in neurodegenerative diseases [19][20][21][22][23][24] and SIGMAR1 mutations are linked to familial amyotrophic lateral sclerosis (ALS) [21,25]. The crystal structure of human SIGMAR1 has been recently solved [26].…”

Section: Introductionmentioning

confidence: 99%

SIGMAR1/Sigma-1 receptor ablation impairs autophagosome clearance

Yang

Shen

et al. 2019

Autophagy

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Autophagosome-lysosome fusion is a common critical step in various forms of macroautophagy/autophagy including mitophagy, the selective degradation of mitochondria. Regulations of this fusion process remain poorly defined. Here we have determined the role of SIGMAR1, a unique endoplasmic reticulum membrane protein. Knockout of Sigmar1 impaired mitochondrial clearance without altering the PINK1-PRKN/Parkin signaling, in mouse retinal explants and cultured cells treated with carbonyl cyanide m-chlorophenyl hydrazone (CCCP) for induction of mitophagy. SIGMAR1 depletion also caused accumulation of autophagosome markers LC3-II and SQSTM1, but did not change the levels of BECN1 and ATG7, proteins associated with autophagosome biogenesis. Lysosomal pH and protease activities were not negatively affected. However, sigmar1 knockout partially compromised autophagosome-lysosome fusion in CCCP-treated NSC34 cells, as revealed by reduced GFP fluorescence quenching of GFP-RFP-LC3-II puncta and co-localization of lysosomes with mitochondria. Furthermore, SIGMAR1 co-immunoprecipitated with ATG14, STX17, and VAMP8 (but not SNAP29), proteins key to autophagosome-lysosome membrane fusion. Re-expressing SIGMAR1 in the null background rescued clearance of mitochondria and autophagosomes. In summary, we started out finding that sigmar1 knockout impaired the clearance of mitochondria and autophagosomes, and then narrowed down the SIGMAR1 modulation to the autophagosome-lysosome fusion step. This study may shed new light on understanding autophagy-associated cyto-protection and disease mechanisms. Abbreviations : APEX2, a genetically engineered peroxidase; BiFC, bimolecule fluorescence complementation; CCCP, a mitophagy inducing compound; CRISPR, clustered regularly interspaced short palindromic repeats; EM, electron microscopy; ER, endoplasmic reticulum; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; SIGMAR1, sigma non-opioid intracellular receptor 1.

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Section: Introductionmentioning

confidence: 99%

SIGMAR1/Sigma-1 receptor ablation impairs autophagosome clearance

Yang

Shen

et al. 2019

Autophagy

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“…Moreover, nearly 40% of all patients are afflicted by as yet unidentified genes . Notably, increasing evidence shows that, regardless of genetic defect, several common events promote the progression of retinal degeneration such as inflammation, oxidative stress, and apoptosis . Although targeting common disease mechanisms, instead of gene‐specific replacement, could not completely eliminate the detrimental effect of RP‐causing gene, it would prolong photoreceptors survival, and the impact will be enormous because photoreceptors loss in RP occurs over decades .…”

Section: Discussionmentioning

confidence: 99%

“…Although RP‐causing gene mutations, the majority of which occur in rod‐specific transcripts, initiate the photoreceptors degeneration, growing evidence indicates that several events, including neuroinflammation and apoptosis, contribute to its progression . Targeting common pathological processes holds promise for prolonging photoreceptor survival of patients late in life.…”

Section: Introductionmentioning

confidence: 99%

Melatonin delays photoreceptor degeneration in a mouse model of autosomal recessive retinitis pigmentosa

Wang

Jin

et al. 2017

Journal of Pineal Research

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Retinitis pigmentosa (RP) comprises a group of incurable inherited retinal degenerations. Targeting common processes, instead of mutation-specific treatment, has proven to be an innovative strategy to combat debilitating retinal degeneration. Growing evidence indicates that melatonin possesses a potent activity against neurodegenerative disorders by mitigating cell damage associated with apoptosis and inflammation. Given the pleiotropic role of melatonin in central nervous system, the aim of the present study was to investigate whether melatonin would afford protection against retinal degeneration in autosomal recessive RP (arRP). Rd10, a well-characterized murine model of human arRP, received daily intraperitoneal injection of melatonin (15 mg/kg) between postnatal day (P) 13 and P30. Retinas treated with melatonin or vehicle were harvested for analysis at P30 and P45, respectively. The findings showed that melatonin could dampen the photoreceptors death and delay consequent retinal degeneration. We also observed that melatonin weakened the expression of glial fibrillary acidic protein (GFAP) in Müller cells. Additionally, melatonin could alleviate retinal inflammatory response visualized by IBA1 staining, which was further corroborated by downregulation of inflammation-related genes, such as tumor necrosis factor alpha (Tnf-α), chemokine (C-C motif) ligand 2 (Ccl2), and chemokine (C-X-C motif) ligand 10 (Cxcl10). These data revealed that melatonin could ameliorate retinal degeneration through potentially attenuating apoptosis, reactive gliosis, and microglial activation in rd10 mice. Moreover, these results suggest melatonin as a promising agent improving photoreceptors survival in human RP.

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“…Polymerase chain reaction was performed at 95°C for 30 seconds, 63°C for 30 seconds, and 72°C for 45 seconds; melt curve analysis confirmed the purity of the end products. Resulting C Q values were normalized to Gapdh and analyzed using the comparative C Q method 31,32 to obtain fold-changes in gene expression. The analysis was performed in triplicate.…”

Section: Methodsmentioning

confidence: 99%

“…21,24,31,32 Forty to 100 μg protein was subjected to SDSPAGE at 100 V and transferred to nitrocellulose membranes at 90 V for 1.5 hours. Membranes were blocked in 5% milk in TBST (1 hour at room temperature), followed by incubation with primary antibodies: goat anti-MTHFR (Abcam, Cambridge, MA, USA; 1:500), rabbit anti-CBS (Cell Signaling, Danvers, MA, USA; 1:250), rabbit anti-CTH (Thermo-Fisher Scientific, Waltham, MA, USA; 1:500), rabbit anti-3MST (Aviva Systems Biology, San Diego, CA, USA; 1:500), rabbit anti-xCT 33 (1:800), and rabbit anti–taurine transporter (TAUT) (Alomone Labs, Jerusalem, Israel; 1:200) in 5% milk in TBST buffer at 4°C overnight.…”

Section: Methodsmentioning

confidence: 99%

Analysis of MTHFR, CBS, Glutathione, Taurine, and Hydrogen Sulfide Levels in Retinas of Hyperhomocysteinemic Mice

Cui

Navneet

Wang

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeHyperhomocysteinemia (Hhcy) is implicated in certain retinal neurovascular diseases, although whether it is causative remains uncertain. In isolated ganglion cells (GCs), mild Hhcy induces profound death, whereas retinal phenotypes in Hhcy mice caused by mutations in remethylation (methylene tetrahydrofolatereductase [Mthfr+/−]) or transsulfuration pathways (cystathionine β-synthase [Cbs+/−]) demonstrate mild GC loss and mild vasculopathy. The current work investigated compensation in vivo of one pathway for the other, and, because the transsulfuration pathway yields cysteine necessary for formation of glutathione (GSH), taurine, and hydrogen sulfide (H2S), they were analyzed also.MethodsRetinas isolated from wild-type (WT), Mthfr+/−, and Cbs+/− mice (12 and 22 weeks) were analyzed for methylene tetrahydrofolate reductase (MTHFR), cystathionine-β-synthase (CBS), and cystathionase (CTH) RNA/protein levels. Retinas were evaluated for levels of reduced:oxidized GSH (GSH:GSSG), Slc7a11 (xCT), taurine, taurine transporter (TAUT), and H2S.ResultsAside from decreased CBS RNA/protein levels in Cbs+/− retinas, there were minimal alterations in remethylation/transsulfuration pathways in the two mutant mice strains. Glutathione and taurine levels in Mthfr+/− and Cbs+/− retinas were similar to WT, which may be due to robust levels of xCT and TAUT in mutant retinas. Interestingly, levels of H2S were markedly increased in retinas of Mthfr+/− and Cbs+/− mice compared with WT.ConclusionsGanglion cell loss and vasculopathy observed in Mthfr+/− and Cbs+/− mouse retinas may be milder than expected, not because of compensatory increases of enzymes in remethylation/transsulfuration pathways, but because downstream transsulfuration pathway products GSH, taurine, and H2S are maintained at robust levels. Elevation of H2S is particularly intriguing owing to neuroprotective properties reported for this gasotransmitter.

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Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration

Cited by 69 publications

References 58 publications

SIGMAR1/Sigma-1 receptor ablation impairs autophagosome clearance

SIGMAR1/Sigma-1 receptor ablation impairs autophagosome clearance

Melatonin delays photoreceptor degeneration in a mouse model of autosomal recessive retinitis pigmentosa

Analysis of MTHFR, CBS, Glutathione, Taurine, and Hydrogen Sulfide Levels in Retinas of Hyperhomocysteinemic Mice

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