Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid.

Abstract:

:Dysregulation of cyclin-dependent kinase 5 (cdk5) per relative concentrations of its activators p35 and p25 is implicated in neurodegenerative diseases. P35 has a short t½ and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t½, promotes aberrant activation of cdk5 and causes abnormal hyperphosphorylation of tau, thus leading to the formation of neurofibrillary tangles. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperone that is implicated in neuronal survival. However, the specific role of the Sig-1R in neurodegeneration is unclear. Here we found that Sig-1Rs regulate proper tau phosphorylation and axon extension by promoting p35 turnover through the receptor's interaction with myristic acid. In Sig-1R-KO neurons, a greater accumulation of p35 is seen, which results from neither elevated transcription of p35 nor disrupted calpain activity, but rather to the slower degradation of p35. In contrast, Sig-1R overexpression causes a decrease of p35. Sig-1R-KO neurons exhibit shorter axons with lower densities. Myristic acid is found here to bind Sig-1R as an agonist that causes the dissociation of Sig-1R from its cognate partner binding immunoglobulin protein. Remarkably, treatment of Sig-1R-KO neurons with exogenous myristic acid mitigates p35 accumulation, diminishes tau phosphorylation, and restores axon elongation. Our results define the involvement of Sig-1Rs in neurodegeneration and provide a mechanistic explanation that Sig-1Rs help maintain proper tau phosphorylation by potentially carrying and providing myristic acid to p35 for enhanced p35 degradation to circumvent the formation of overreactive cdk5/p25.

authors

Tsai SY,Pokrass MJ,Klauer NR,Nohara H,Su TP

doi

10.1073/pnas.1422001112

subject

Has Abstract

pub_date

2015-05-26 00:00:00

pages

6742-7

issue

21

eissn

0027-8424

issn

1091-6490

pii

1422001112

journal_volume

112

pub_type

杂志文章
  • Observing the formation of ice and organic crystals in active sites.

    abstract::Heterogeneous nucleation is vital to a wide range of areas as diverse as ice nucleation on atmospheric aerosols and the fabrication of high-performance thin films. There is excellent evidence that surface topography is a key factor in directing crystallization in real systems; however, the mechanisms by which nanoscal...

    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.1617717114

    authors: Campbell JM,Meldrum FC,Christenson HK

    更新日期:2017-01-31 00:00:00

  • Gallstones play a significant role in Salmonella spp. gallbladder colonization and carriage.

    abstract::Salmonella enterica serovar Typhi can colonize the gallbladder and persist in an asymptomatic carrier state that is frequently associated with the presence of gallstones. We have shown that salmonellae form bile-mediated biofilms on human gallstones and cholesterol-coated surfaces in vitro. Here, we test the hypothesi...

    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.1000862107

    authors: Crawford RW,Rosales-Reyes R,Ramírez-Aguilar Mde L,Chapa-Azuela O,Alpuche-Aranda C,Gunn JS

    更新日期:2010-03-02 00:00:00

  • Adeno-associated virus (AAV) Rep proteins mediate complex formation between AAV DNA and its integration site in human DNA.

    abstract::AAV is unique among eukaryotic viruses in the ability of its DNA to integrate preferentially into a specific region of the human genome. Understanding AAV integration may aid in developing gene therapy systems with predictable integration sites. Using a gel mobility-shift assay, we have identified a DNA sequence withi...

    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.91.13.5808

    authors: Weitzman MD,Kyöstiö SR,Kotin RM,Owens RA

    更新日期:1994-06-21 00:00:00

  • 31P nuclear magnetic relaxation studies of phosphocreatine in intact muscle: determination of intracellular free magnesium.

    abstract::31P nuclear magnetic relaxation rates for phosphocreatine in intact frog gastrocnemius were compared with those observed in model solutions at 4 degrees, a temperature at which muscle maintains its physiological state for at least 5 hr. Both nuclear Overhauser effect and spin-lattice relaxation rate (1/T1) experiments...

    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.74.10.4271

    authors: Cohen SM,Burt CT

    更新日期:1977-10-01 00:00:00

  • Time-resolved x-ray diffraction reveals multiple conformations in the M-N transition of the bacteriorhodopsin photocycle.

    abstract::We measured the M-N transition of wild-type bacteriorhodopsin (pH 9, 10 degrees C) by time-resolved x-ray diffraction study at SPring8 BL45XU-A. We confirmed the accumulation of M and N intermediates by absorbance measurements, and we found that the time resolution of x-ray diffraction experiments (244 ms) was suffici...

    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.260504897

    authors: Oka T,Yagi N,Fujisawa T,Kamikubo H,Tokunaga F,Kataoka M

    更新日期:2000-12-19 00:00:00

  • Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor.

    abstract::The highly aggressive character of melanoma makes it an excellent model for probing the mechanisms underlying metastasis, which remains one of the most difficult challenges in treating cancer. We find that miR-182, member of a miRNA cluster in a chromosomal locus (7q31-34) frequently amplified in melanoma, is commonly...

    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.0808263106

    authors: Segura MF,Hanniford D,Menendez S,Reavie L,Zou X,Alvarez-Diaz S,Zakrzewski J,Blochin E,Rose A,Bogunovic D,Polsky D,Wei J,Lee P,Belitskaya-Levy I,Bhardwaj N,Osman I,Hernando E

    更新日期:2009-02-10 00:00:00

  • Rationing social contact during the COVID-19 pandemic: Transmission risk and social benefits of US locations.

    abstract::To prevent the spread of coronavirus disease 2019 (COVID-19), some types of public spaces have been shut down while others remain open. These decisions constitute a judgment about the relative danger and benefits of those locations. Using mobility data from a large sample of smartphones, nationally representative cons...

    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.2008025117

    authors: Benzell SG,Collis A,Nicolaides C

    更新日期:2020-06-30 00:00:00

  • Early tertiary elephant-shrews from Egypt and the origin of the Macroscelidea.

    abstract::Recent expeditions to the Fayum Depression, Egypt, have made possible the discovery of mandibles and a maxilla of a new genus and species of late Eocene elephant-shrew as well as initial evidence of the upper dentition of the early Oligocene taxon Metoldobotes. These fossils demonstrate that macroscelideans underwent ...

    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.88.21.9734

    authors: Simons EL,Holroyd PA,Bown TM

    更新日期:1991-11-01 00:00:00

  • Protective hinge in insulin opens to enable its receptor engagement.

    abstract::Insulin provides a classical model of a globular protein, yet how the hormone changes conformation to engage its receptor has long been enigmatic. Interest has focused on the C-terminal B-chain segment, critical for protective self-assembly in β cells and receptor binding at target tissues. Insight may be obtained fro...

    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.1412897111

    authors: Menting JG,Yang Y,Chan SJ,Phillips NB,Smith BJ,Whittaker J,Wickramasinghe NP,Whittaker LJ,Pandyarajan V,Wan ZL,Yadav SP,Carroll JM,Strokes N,Roberts CT Jr,Ismail-Beigi F,Milewski W,Steiner DF,Chauhan VS,Ward CW,Weis

    更新日期:2014-08-19 00:00:00

  • Human monoclonal antibodies produced by primary in vitro immunization of peripheral blood lymphocytes.

    abstract::A general procedure is described for the production of human monoclonal antibodies from peripheral blood lymphocytes immunized in vitro against T-cell-dependent antigens. These lymphocytes immunized in culture were used to produce human-human or human-mouse hybridomas secreting monoclonal antibodies specific for digox...

    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.85.11.3995

    authors: Borrebaeck CA,Danielsson L,Möller SA

    更新日期:1988-06-01 00:00:00

  • Requirement of proteins S5 and S9 from 30S subunits for the ribosome-dependent GTPase activity of elongation factor G.

    abstract::During CsCl isopycnic centrifugation at 20 mM Mg(++), Escherichia coli 30S ribosomal subunits specifically lose proteins S1, S2, S3, S5, S9, S10, and S14. The resultant 30S core is unable to stimulate the GTPase activity of EF-G in the presence of 50S subunits. Activity could be restored to a small extent by adding ba...

    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.70.1.151

    authors: Marsh RC,Parmeggiani A

    更新日期:1973-01-01 00:00:00

  • Structural studies of the scrapie prion protein by electron crystallography.

    abstract::Because the insolubility of the scrapie prion protein (PrP(Sc)) has frustrated structural studies by x-ray crystallography or NMR spectroscopy, we used electron crystallography to characterize the structure of two infectious variants of the prion protein. Isomorphous two-dimensional crystals of the N-terminally trunca...

    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.052703499

    authors: Wille H,Michelitsch MD,Guenebaut V,Supattapone S,Serban A,Cohen FE,Agard DA,Prusiner SB

    更新日期:2002-03-19 00:00:00

  • In vivo X-ray cine-tomography for tracking morphological dynamics.

    abstract::Scientific cinematography using ultrafast optical imaging is a common tool to study motion. In opaque organisms or structures, X-ray radiography captures sequences of 2D projections to visualize morphological dynamics, but for many applications full four-dimensional (4D) spatiotemporal information is highly desirable....

    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.1308650111

    authors: dos Santos Rolo T,Ershov A,van de Kamp T,Baumbach T

    更新日期:2014-03-18 00:00:00

  • Perilipins 2 and 3 lack a carboxy-terminal domain present in perilipin 1 involved in sequestering ABHD5 and suppressing basal lipolysis.

    abstract::Lipid droplets (LDs) are a conserved feature of most organisms. Vertebrate adipocytes have evolved to efficiently store and release lipids for the whole organism from a single droplet. Perilipin 1, the most abundant lipid-coat protein in adipocytes, plays a key role in regulating lipolysis. In other tissues such as li...

    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.1318791111

    authors: Patel S,Yang W,Kozusko K,Saudek V,Savage DB

    更新日期:2014-06-24 00:00:00

  • A cloned cyanobacterial gene for glutamine synthetase functions in Escherichia coli, but the enzyme is not adenylylated.

    abstract::The coding sequence for Anabaena 7120 glutamine synthetase [L-glutamate:ammonia ligase (ADP-forming), EC 6.3.1.1] are shown to be contained within a 7.5-kilobase-pair (kbp) HindIII fragment that has been cloned by plaque hybridization. The hybridization probe for the cyanobacterial gene was a recombinant plasmid conta...

    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.78.6.3393

    authors: Fisher R,Tuli R,Haselkorn R

    更新日期:1981-06-01 00:00:00

  • Myc represses transcription of the growth arrest gene gas1.

    abstract::Cell proliferation is regulated by the induction of growth promoting genes and the suppression of growth inhibitory genes. Malignant growth can result from the altered balance of expression of these genes in favor of cell proliferation. Induction of the transcription factor, c-Myc, promotes cell proliferation and tran...

    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.94.24.12886

    authors: Lee TC,Li L,Philipson L,Ziff EB

    更新日期:1997-11-25 00:00:00

  • Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt.

    abstract::Toll like receptors (TLRs) use Toll-IL-1 receptor (TIR) domain-containing adapters, such as myeloid differentiation primary response gene 88 (MyD88) and TIR domain-containing adapter inducing IFN-β (TRIF), to induce activation of transcription factors, including NF-κB, MAP kinases, and IFN regulatory factors. TLR sign...

    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.1118579109

    authors: Troutman TD,Hu W,Fulenchek S,Yamazaki T,Kurosaki T,Bazan JF,Pasare C

    更新日期:2012-01-03 00:00:00

  • Nerve growth factor: activation of the classical complement pathway by specific substitution for component C1-.

    abstract::The interaction of homogeneous preparations of mouse submandibular gland nerve growth factor (NGF) with the classical complement pathway was studied. NGF was found to be capable of carrying out the enzyme activities of the first component (C1-) of the classical complement pathway (i.e., the cleavage of zymogen C4 and ...

    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.79.8.2519

    authors: Boyle MD,Young M

    更新日期:1982-04-01 00:00:00

  • Identification of 5,8-oxyretinoic acid isolated from small intestine of vitamin A-deficient rats dosed with retinoic acid.

    abstract::A retinoid was isolated by a multistep procedure from the small intestines of vitamin A-deficient rats given a single dose of retinoic acid. The compound, designated 8II, was pure, as demonstrated by four high-pressure liquid chromatographic procedures. It was positively identified as 5,8-oxyretinoic acid by ultraviol...

    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.75.6.2603

    authors: Napoli JL,McCormick AM,Schnoes HK,DeLuca HF

    更新日期:1978-06-01 00:00:00

  • Expression of a bovine rhodopsin gene in Xenopus oocytes: demonstration of light-dependent ionic currents.

    abstract::Xenopus oocytes express a gene encoding bovine rhodopsin as well as its SP6 RNA polymerase-derived transcripts and total retinal mRNA. The opsin produced is in unglycosylated (30 kDa) and two glycosylated (35 kDa and 41 kDa) forms. Incubation of the cells expressing the above proteins with 11-cis-retinal generates rho...

    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.85.21.7917

    authors: Khorana HG,Knox BE,Nasi E,Swanson R,Thompson DA

    更新日期:1988-11-01 00:00:00

  • Dielectric constant of atomic fluids with variable polarizability.

    abstract::The Clausius-Mossotti function for the dielectric constant is expanded in terms of single atom and pair polarizabilities, leading to contributions that depend on both the trace and the anisotropy of the pair-polarizability tensor. The short-range contribution of the anisotropic part to the pair polarizabilities has pr...

    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.77.6.3098

    authors: Alder BJ,Beers JC,Strauss HL,Weis JJ

    更新日期:1980-06-01 00:00:00

  • Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features.

    abstract::Diminished Sonic Hedgehog (Shh) signaling is associated with the most common forebrain defect in humans, holoprosencephaly (HPE), which includes cyclopia, a phenotype also seen in mice and other vertebrates with defective Shh signaling. The secreted protein Shh acts as a crucial factor that patterns the ventral forebr...

    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.2235734100

    authors: Roessler E,Du YZ,Mullor JL,Casas E,Allen WP,Gillessen-Kaesbach G,Roeder ER,Ming JE,Ruiz i Altaba A,Muenke M

    更新日期:2003-11-11 00:00:00

  • Molecular determinants of tissue selectivity in estrogen receptor modulators.

    abstract::Interaction of the estrogen receptor/ligand complex with a DNA estrogen response element is known to regulate gene transcription. In turn, specific conformations of the receptor-ligand complex have been postulated to influence unique subsets of estrogen-responsive genes resulting in differential modulation and, ultima...

    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.94.25.14105

    authors: Grese TA,Sluka JP,Bryant HU,Cullinan GJ,Glasebrook AL,Jones CD,Matsumoto K,Palkowitz AD,Sato M,Termine JD,Winter MA,Yang NN,Dodge JA

    更新日期:1997-12-09 00:00:00

  • Secretion of catecholamines from adrenal gland by a single electrical shock: electronic depolarization of medullary cell membrane.

    abstract::Transmural stimulation of the isolated adrenal gland of the rat and guinea pig results in secretion of catecholamine. The secretion is due to activation of cholinergic receptors of the adrenal medulla by acetylcholine released from splanchnic nerve terminals after transmural stimulation. Our aim was to see whether the...

    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.79.9.3071

    authors: Wakade AR,Wakade TD

    更新日期:1982-05-01 00:00:00

  • Dual role of lignin in plant litter decomposition in terrestrial ecosystems.

    abstract::Plant litter decomposition is a critical step in the formation of soil organic matter, the mineralization of organic nutrients, and the carbon balance in terrestrial ecosystems. Biotic decomposition in mesic ecosystems is generally negatively correlated with the concentration of lignin, a group of complex aromatic pol...

    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.0909396107

    authors: Austin AT,Ballaré CL

    更新日期:2010-03-09 00:00:00

  • Cell envelope and shape of Escherichia coli K12. Crosslinking with dimethyl imidoesters of the whole cell wall.

    abstract::E. coli cells treated with the bifunctional crosslinking reagents dimethyl malonimidate, succinimidate, adipimidate, suberimidate, and sebacinimidate served for the isolation of rod-shaped "ghosts." These ghosts proved to be crosslinked over their entire surface; i.e., a macromolecule (resistant to boiling 1% Na dodec...

    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.71.5.2018

    authors: Haller I,Henning U

    更新日期:1974-05-01 00:00:00

  • Effects of past, present, and future ocean carbon dioxide concentrations on the growth and survival of larval shellfish.

    abstract::The combustion of fossil fuels has enriched levels of CO(2) in the world's oceans and decreased ocean pH. Although the continuation of these processes may alter the growth, survival, and diversity of marine organisms that synthesize CaCO(3) shells, the effects of ocean acidification since the dawn of the industrial re...

    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.0913804107

    authors: Talmage SC,Gobler CJ

    更新日期:2010-10-05 00:00:00

  • Insulin binding and insulin action in cultured fibroblasts: significant differences between a phosphoglucose isomerase-deficient mutant and the parental strain.

    abstract::The interrelationships of hexose feeding and insulin action were studied in the Chinese hamster fibroblast cell lines 023 and DS-7. The latter, derived from 023 and deficient in phosphoglucose isomerase, has been used to map the metabolic requirements for aldohexose-mediated down-regulation or "curbing" of hexose tran...

    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.83.11.3684

    authors: Wilson C,Peterson SW,Ullrey DB,Kalckar HM

    更新日期:1986-06-01 00:00:00

  • Electron microscope study of the kinetics of the fiber-to-crystal transition of sickle cell hemoglobin.

    abstract::The intermediates and the rate-limiting step in the crystallization of deoxygenated sickle hemoglobin have been determined by a kinetic study with the use of electron microscopy. In slowly stirred solutions of deoxygenated hemoglobin S [Pumphrey, J. & Steinhardt, J. (1977) J. Mol. Biol. 112, 359--375], the sequential ...

    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.77.2.944

    authors: Wilson SM,Makinen MW

    更新日期:1980-02-01 00:00:00

  • Tests of parallel molecular evolution in a long-term experiment with Escherichia coli.

    abstract::The repeatability of evolutionary change is difficult to quantify because only a single outcome can usually be observed for any precise set of circumstances. In this study, however, we have quantified the frequency of parallel and divergent genetic changes in 12 initially identical populations of Escherichia coli that...

    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.0602917103

    authors: Woods R,Schneider D,Winkworth CL,Riley MA,Lenski RE

    更新日期:2006-06-13 00:00:00