Genetic rescue models refute nonautonomous rod cell death in retinitis pigmentosa.

Abstract:

:Retinitis pigmentosa (RP) is an inherited neurodegenerative disease, in which the death of mutant rod photoreceptors leads secondarily to the non-cell autonomous death of cone photoreceptors. Gene therapy is a promising treatment strategy. Unfortunately, current methods of gene delivery treat only a fraction of diseased cells, yielding retinas that are a mosaic of treated and untreated rods, as well as cones. In this study, we created two RP mouse models to test whether dying, untreated rods negatively impact treated, rescued rods. In one model, treated and untreated rods were segregated. In the second model, treated and untreated rods were diffusely intermixed, and their ratio was controlled to achieve low-, medium-, or high-efficiency rescue. Analysis of these mosaic retinas demonstrated that rescued rods (and cones) survive, even when they are greatly outnumbered by dying photoreceptors. On the other hand, the rescued photoreceptors did exhibit long-term defects in their outer segments (OSs), which were less severe when more photoreceptors were treated. In summary, our study suggests that even low-efficiency gene therapy may achieve stable survival of rescued photoreceptors in RP patients, albeit with OS dysgenesis.

authors

Koch SF,Duong JK,Hsu CW,Tsai YT,Lin CS,Wahl-Schott CA,Tsang SH

doi

10.1073/pnas.1615394114

subject

Has Abstract

pub_date

2017-05-16 00:00:00

pages

5259-5264

issue

20

eissn

0027-8424

issn

1091-6490

pii

1615394114

journal_volume

114

pub_type

杂志文章
  • The Role of 1N-Ethenoadenosine Triphosphate and 1N-Ethenoadenosine Monophosphate in Firefly Luminescence.

    abstract::1,N(6)-Ethenoadenosine triphosphate (epsilon-ATP) has been found to be inactive as a substrate for firefly luciferase. However, chemically synthesized luciferyl-epsilonAMP is oxidized by luciferase and light is emitted. The color of the light is red in contrast to the normal yellow-green observed with luciferyladenyla...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.70.6.1664

    authors: Deluca M,Leonard NJ,Gates BJ,McElroy WD

    更新日期:1973-06-01 00:00:00

  • Aberration-corrected cryoimmersion light microscopy.

    abstract::Cryogenic fluorescent light microscopy of flash-frozen cells stands out by artifact-free fixation and very little photobleaching of the fluorophores used. To attain the highest level of resolution, aberration-free immersion objectives with accurately matched immersion media are required, but both do not exist for imag...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1717282115

    authors: Faoro R,Bassu M,Mejia YX,Stephan T,Dudani N,Boeker C,Jakobs S,Burg TP

    更新日期:2018-02-06 00:00:00

  • A short 5'-flanking DNA region is sufficient for developmentally correct expression of moth chorion genes in Drosophila.

    abstract::Fusions with the bacterial gene for chloramphenicol acetyltransferase followed by P-element-mediated germ-line transformation in Drosophila have permitted localization of the DNA sequence that confers a high degree of developmental specificity on a pair of silkmoth eggshell (chorion) genes. The short, 272-base-pair, 5...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.84.22.7987

    authors: Mitsialis SA,Spoerel N,Leviten M,Kafatos FC

    更新日期:1987-11-01 00:00:00

  • BMP-SMAD-ID promotes reprogramming to pluripotency by inhibiting p16/INK4A-dependent senescence.

    abstract::Fibrodysplasia ossificans progressiva (FOP) patients carry a missense mutation in ACVR1 [617G > A (R206H)] that leads to hyperactivation of BMP-SMAD signaling. Contrary to a previous study, here we show that FOP fibroblasts showed an increased efficiency of induced pluripotent stem cell (iPSC) generation. This positiv...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1603668113

    authors: Hayashi Y,Hsiao EC,Sami S,Lancero M,Schlieve CR,Nguyen T,Yano K,Nagahashi A,Ikeya M,Matsumoto Y,Nishimura K,Fukuda A,Hisatake K,Tomoda K,Asaka I,Toguchida J,Conklin BR,Yamanaka S

    更新日期:2016-11-15 00:00:00

  • MDC1 regulates intra-S-phase checkpoint by targeting NBS1 to DNA double-strand breaks.

    abstract::The product of the Nijmegen breakage syndrome gene (NBS1) plays crucial roles in DNA damage response through its association with many proteins, including MRE11 and RAD50. However, it remains to be determined exactly how NBS1 accumulates at or near DNA double-strand breaks. Here we report that MDC1 directly binds to N...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0802885105

    authors: Wu L,Luo K,Lou Z,Chen J

    更新日期:2008-08-12 00:00:00

  • Circadian clock-controlled genes isolated from Neurospora crassa are late night- to early morning-specific.

    abstract::An endogenous circadian biological clock controls the temporal aspects of life in most organisms, including rhythmic control of genes involved in clock output pathways. In the fungus Neurospora crassa, one pathway known to be under control of the clock is asexual spore (conidia) development. To understand more fully t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.93.23.13096

    authors: Bell-Pedersen D,Shinohara ML,Loros JJ,Dunlap JC

    更新日期:1996-11-12 00:00:00

  • Human bone marrow and umbilical cord blood cells generate CD4+ and CD8+ single-positive T cells in murine fetal thymus organ culture.

    abstract::Murine fetal thymus lobes isolated from both normal and scid/scid mice can be colonized by donor cells from either human bone marrow or human umbilical cord blood in vitro. Subsequent organ culture results in a transient production of a few CD4+ CD8+ (double-positive) cells and then the accumulation of CD4+ or CD8+ (s...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.90.22.10778

    authors: Yeoman H,Gress RE,Bare CV,Leary AG,Boyse EA,Bard J,Shultz LD,Harris DT,DeLuca D

    更新日期:1993-11-15 00:00:00

  • Hydrodynamic collective effects of active protein machines in solution and lipid bilayers.

    abstract::The cytoplasm and biomembranes in biological cells contain large numbers of proteins that cyclically change their shapes. They are molecular machines that can function as molecular motors or carry out various other tasks in the cell. Many enzymes also undergo conformational changes within their turnover cycles. We ana...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1506825112

    authors: Mikhailov AS,Kapral R

    更新日期:2015-07-14 00:00:00

  • Selective targeting of gene products with the megakaryocyte platelet factor 4 promoter.

    abstract::We have used the 1.1 kilobases of the 5' upstream region of the platelet factor four (PF4) gene coupled to the prokaryotic beta-galactosidase gene to generate two lines of transgenic mice that express this construct. Studies of blood, bone marrow, spleen, and thymus reveal that platelets are the only circulating blood...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.88.4.1521

    authors: Ravid K,Beeler DL,Rabin MS,Ruley HE,Rosenberg RD

    更新日期:1991-02-15 00:00:00

  • Aggregation-triggering segments of SOD1 fibril formation support a common pathway for familial and sporadic ALS.

    abstract::ALS is a terminal disease of motor neurons that is characterized by accumulation of proteinaceous deposits in affected cells. Pathological deposition of mutated Cu/Zn superoxide dismutase (SOD1) accounts for ∼20% of the familial ALS (fALS) cases. However, understanding the molecular link between mutation and disease h...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1320786110

    authors: Ivanova MI,Sievers SA,Guenther EL,Johnson LM,Winkler DD,Galaleldeen A,Sawaya MR,Hart PJ,Eisenberg DS

    更新日期:2014-01-07 00:00:00

  • Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia.

    abstract::Morphine produces analgesia at opiate receptors expressed in nociceptive circuits. mu, delta, and kappa opiate receptor subtypes are expressed in circuits that can modulate nociception and receive inputs from endogenous opioid neuropeptide ligands. The roles played by each receptor subtype in nociceptive processing in...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.94.4.1544

    authors: Sora I,Takahashi N,Funada M,Ujike H,Revay RS,Donovan DM,Miner LL,Uhl GR

    更新日期:1997-02-18 00:00:00

  • Depression of cytidine 3':5'-cyclic monophosphate phosphodiesterase activity in developing tissues of guinea pigs.

    abstract::Changes in levels of the newly discovered cytidine 3':5'-cyclic monophosphate (cyclic CMP) phosphodiesterase in some representative tissues (cerebral cortex, kidney, intestine, liver, heart, and lung) of guinea pigs from various developmental stages (fetus, neonate, pup, and adult) were studied and compared with those...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.75.9.4422

    authors: Helfman DM,Brackett NL,Kuo JF

    更新日期:1978-09-01 00:00:00

  • Heme transfer to the heme chaperone CcmE during cytochrome c maturation requires the CcmC protein, which may function independently of the ABC-transporter CcmAB.

    abstract::Cytochrome c maturation in Escherichia coli requires the ccm operon, which encodes eight membrane proteins (CcmABCDEFGH). CcmE is a periplasmic heme chaperone that binds heme covalently and transfers it onto apocytochrome c in the presence of CcmF, CcmG, and CcmH. In this work we addressed the functions of the ccmABCD...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.96.11.6462

    authors: Schulz H,Fabianek RA,Pellicioli EC,Hennecke H,Thöny-Meyer L

    更新日期:1999-05-25 00:00:00

  • Enhancement of translation by the downstream box does not involve base pairing of mRNA with the penultimate stem sequence of 16S rRNA.

    abstract::The downstream box (DB) is a sequence element that enhances translation of several bacterial and phage mRNAs. It has been proposed that the DB enhances translation by base pairing transiently to bases 1469-1483 of 16S rRNA, the so-called anti-DB, during the initiation phase of translation. We have tested this model of...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.96.16.8973

    authors: O'Connor M,Asai T,Squires CL,Dahlberg AE

    更新日期:1999-08-03 00:00:00

  • GBA1 deficiency negatively affects physiological α-synuclein tetramers and related multimers.

    abstract::Accumulating evidence suggests that α-synuclein (α-syn) occurs physiologically as a helically folded tetramer that resists aggregation. However, the mechanisms underlying the regulation of formation of α-syn tetramers are still mostly unknown. Cellular membrane lipids are thought to play an important role in the regul...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1700465115

    authors: Kim S,Yun SP,Lee S,Umanah GE,Bandaru VVR,Yin X,Rhee P,Karuppagounder SS,Kwon SH,Lee H,Mao X,Kim D,Pandey A,Lee G,Dawson VL,Dawson TM,Ko HS

    更新日期:2018-01-23 00:00:00

  • Antibody-induced uncoating of human rhinovirus B14.

    abstract::Rhinoviruses (RVs) are the major causes of common colds in humans. They have a nonenveloped, icosahedral capsid surrounding a positive-strand RNA genome. Here we report that the antigen-binding (Fab) fragment of a neutralizing antibody (C5) can trigger genome release from RV-B14 to form emptied particles and neutraliz...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1707369114

    authors: Dong Y,Liu Y,Jiang W,Smith TJ,Xu Z,Rossmann MG

    更新日期:2017-07-25 00:00:00

  • Regulation of ferritin and heme oxygenase synthesis in rat fibroblasts by different forms of iron.

    abstract::Synthesis of the iron-storage protein ferritin is thought to be regulated at the translational level by the cytosolic content of chelatable iron. This response to iron is regulated by the iron-modulated binding to ferritin mRNAs of a repressor protein, the iron regulatory element-binding protein. From measurements mad...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.88.3.688

    authors: Eisenstein RS,Garcia-Mayol D,Pettingell W,Munro HN

    更新日期:1991-02-01 00:00:00

  • Tug-of-war as a cooperative mechanism for bidirectional cargo transport by molecular motors.

    abstract::Intracellular transport is based on molecular motors that pull cargos along cytoskeletal filaments. One motor species always moves in one direction, e.g., conventional kinesin moves to the microtubule plus end, whereas cytoplasmic dynein moves to the microtubule minus end. However, many cellular cargoes are observed t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0706825105

    authors: Müller MJ,Klumpp S,Lipowsky R

    更新日期:2008-03-25 00:00:00

  • Recent assembly of the Cerrado, a neotropical plant diversity hotspot, by in situ evolution of adaptations to fire.

    abstract::The relative importance of local ecological and larger-scale historical processes in causing differences in species richness across the globe remains keenly debated. To gain insight into these questions, we investigated the assembly of plant diversity in the Cerrado in South America, the world's most species-rich trop...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0903410106

    authors: Simon MF,Grether R,de Queiroz LP,Skema C,Pennington RT,Hughes CE

    更新日期:2009-12-01 00:00:00

  • Free-energy landscape of protein oligomerization from atomistic simulations.

    abstract::In the realm of protein-protein interactions, the assembly process of homooligomers plays a fundamental role because the majority of proteins fall into this category. A comprehensive understanding of this multistep process requires the characterization of the driving molecular interactions and the transient intermedia...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1320077110

    authors: Barducci A,Bonomi M,Prakash MK,Parrinello M

    更新日期:2013-12-03 00:00:00

  • On the transfer of information from old to new chains of DNA duplexes in phage lambda: destruction of heterozygotes.

    abstract::The Watson-Crick model for DNA duplex duplication proposes that the two parental chains separate and that each directs the synthesis of a complementary chain with which it is found associated after the duplication act. Previous experiments have left unchallenged alternative models which propose that in any single act ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.65.2.363

    authors: Russo VE,Stahl MM,Stahl FW

    更新日期:1970-02-01 00:00:00

  • A functional peptide encoded in the Escherichia coli 23S rRNA.

    abstract::A pentapeptide open reading frame equipped with a canonical ribosome-binding site is present in the Escherichia coli 23S rRNA. Overexpression of 23S rRNA fragments containing the mini-gene renders cells resistant to the ribosome-inhibiting antibiotic erythromycin. Mutations that change either the initiator or stop cod...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.93.11.5641

    authors: Tenson T,DeBlasio A,Mankin A

    更新日期:1996-05-28 00:00:00

  • Airborne methane remote measurements reveal heavy-tail flux distribution in Four Corners region.

    abstract::Methane (CH4) impacts climate as the second strongest anthropogenic greenhouse gas and air quality by influencing tropospheric ozone levels. Space-based observations have identified the Four Corners region in the Southwest United States as an area of large CH4 enhancements. We conducted an airborne campaign in Four Co...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1605617113

    authors: Frankenberg C,Thorpe AK,Thompson DR,Hulley G,Kort EA,Vance N,Borchardt J,Krings T,Gerilowski K,Sweeney C,Conley S,Bue BD,Aubrey AD,Hook S,Green RO

    更新日期:2016-08-30 00:00:00

  • Human cytomegalovirus haplotype reconstruction reveals high diversity due to superinfection and evidence of within-host recombination.

    abstract::Recent sequencing efforts have led to estimates of human cytomegalovirus (HCMV) genome-wide intrahost diversity that rival those of persistent RNA viruses [Renzette N, Bhattacharjee B, Jensen JD, Gibson L, Kowalik TF (2011) PLoS Pathog 7:e1001344]. Here, we deep sequence HCMV genomes recovered from single and longitud...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1818130116

    authors: Cudini J,Roy S,Houldcroft CJ,Bryant JM,Depledge DP,Tutill H,Veys P,Williams R,Worth AJJ,Tamuri AU,Goldstein RA,Breuer J

    更新日期:2019-03-19 00:00:00

  • Benzodiazepine/gamma-aminobutyric acid receptor deficit in the midbrain of the seizure-susceptible gerbil.

    abstract::The density of benzodiazepine/gamma-aminobutyric acid receptor binding sites was lower in the midbrain of seizure-susceptible gerbils compared to control seizure-resistant gerbils. Binding of [3H]diazepam to high-affinity brain-specific sites in membrane homogenates of gerbil brain showed a 20-30% lower binding in mid...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.82.19.6701

    authors: Olsen RW,Wamsley JK,McCabe RT,Lee RJ,Lomax P

    更新日期:1985-10-01 00:00:00

  • TOR dynamically regulates plant cell-cell transport.

    abstract::The coordinated redistribution of sugars from mature "source" leaves to developing "sink" leaves requires tight regulation of sugar transport between cells via plasmodesmata (PD). Although fundamental to plant physiology, the mechanisms that control PD transport and thereby support development of new leaves have remai...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1919196117

    authors: Brunkard JO,Xu M,Scarpin MR,Chatterjee S,Shemyakina EA,Goodman HM,Zambryski P

    更新日期:2020-03-03 00:00:00

  • Molecular determinants of drug access to the receptor site for antiarrhythmic drugs in the cardiac Na+ channel.

    abstract::The clinical efficacy of local anesthetic and antiarrhythmic drugs is due to their voltage- and frequency-dependent block of Na+ channels. Quaternary local anesthetic analogs such as QX-314, which are permanently charged and membrane-impermeant, effectively block cardiac Na+ channels when applied from either side of t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.25.11839

    authors: Qu Y,Rogers J,Tanada T,Scheuer T,Catterall WA

    更新日期:1995-12-05 00:00:00

  • DNA methyltransferase 3B regulates duration of neural crest production via repression of Sox10.

    abstract::Neural crest stem cells arise within the central nervous system but then undergo an epithelial-to-mesenchymal transition to migrate away and contribute to the peripheral nervous system and craniofacial skeleton. Here we show that DNA methyltransferase 3B (DNMT3B) is responsible for the loss of competence of dorsal neu...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1318408111

    authors: Hu N,Strobl-Mazzulla PH,Simoes-Costa M,Sánchez-Vásquez E,Bronner ME

    更新日期:2014-12-16 00:00:00

  • Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration.

    abstract::Fluorescent bisretinoids, such as A2E and all-trans-retinal dimer, form as a by-product of vitamin A cycling in retina and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin pigments. These pigments are implicated in pathological mechanisms involved in several vision-threatening diseases including age-...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0913112107

    authors: Wu Y,Yanase E,Feng X,Siegel MM,Sparrow JR

    更新日期:2010-04-20 00:00:00

  • Nutritional impact of elevated calcium transport activity in carrots.

    abstract::Nutrition recommendations worldwide emphasize ingestion of plant-based diets rather than diets that rely primarily on animal products. However, this plant-based diet could limit the intake of essential nutrients such as calcium. Osteoporosis is one of the world's most prevalent nutritional disorders, and inadequate di...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章,随机对照试验

    doi:10.1073/pnas.0709005105

    authors: Morris J,Hawthorne KM,Hotze T,Abrams SA,Hirschi KD

    更新日期:2008-02-05 00:00:00