Pin1 Modulates the Synaptic Content of NMDA Receptors via Prolyl-Isomerization of PSD-95

Phosphorylation of serine/threonine residues preceding a proline regulates the fate of its targets through postphosphorylation conformational changes catalyzed by the peptidyl-prolyl cis-/trans isomerase Pin1. By flipping the substrate between two different functional conformations, this enzyme exerts a fine-tuning of phosphorylation signals. Pin1 has been detected in dendritic spines and shafts where it regulates protein synthesis required to sustain the late phase of long-term potentiation (LTP). Here, we demonstrate that Pin1 residing in postsynaptic structures can interact with postsynaptic density protein-95 (PSD-95), a key scaffold protein that anchors NMDA receptors (NMDARs) in PSD via GluN2-type receptor subunits. Pin1 recruitment by PSD-95 occurs at specific serine-threonine/proline consensus motifs localized in the linker region connecting PDZ2 to PDZ3 domains. Upon binding, Pin1 triggers structural changes in PSD-95, thus negatively affecting its ability to interact with NMDARs. In electrophysiological experiments, larger NMDA-mediated synaptic currents, evoked in CA1 principal cells by Schaffer collateral stimulation, were detected in hippocampal slices obtained from Pin1(-/-) mice compared with controls. Similar results were obtained in cultured hippocampal cells expressing a PSD-95 mutant unable to undergo prolyl-isomerization, thus indicating that the action of Pin1 on PSD-95 is critical for this effect. In addition, an enhancement in spine density and size was detected in CA1 principal cells of Pin1(-/-) or in Thy-1GFP mice treated with the pharmacological inhibitor of Pin1 catalytic activity PiB.Our data indicate that Pin1 controls synaptic content of NMDARs via PSD-95 prolyl-isomerization and the expression of dendritic spines, both required for LTP maintenance

Mechanisms by which autophagy regulates memory capacity in ageing

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X-Ray Polarization Observations of BL Lacertae

Full list of authors: Middei, Riccardo; Liodakis, Ioannis; Perri, Matteo; Puccetti, Simonetta; Cavazzuti, Elisabetta; Di Gesu, Laura; Ehlert, Steven R.; Madejski, Grzegorz; Marscher, Alan P.; Marshall, Herman L.; Muleri, Fabio; Negro, Michela; Jorstad, Svetlana G.; Agis-Gonzalez, Beatriz; Agudo, Ivan; Bonnoli, Giacomo; Bernardos, Maria, I; Casanova, Victor; Garcia-Comas, Maya; Husillos, Cesar; Marchini, Alessandro; Sota, Alfredo; Kouch, Pouya M.; Lindfors, Elina; Borman, George A.; Kopatskaya, Evgenia N.; Larionova, Elena G.; Morozova, Daria A.; Savchenko, Sergey S.; Vasilyev, Andrey A.; Zhovtan, Alexey, V; Casadio, Carolina; Escudero, Juan; Myserlis, Ioannis; Hales, Antonio; Kameno, Seiji; Kneissl, Ruediger; Messias, Hugo; Nagai, Hiroshi; Blinov, Dmitry; Bourbah, Ioakeim G.; Kiehlmann, Sebastian; Kontopodis, Evangelos; Mandarakas, Nikos; Romanopoulos, Stylianos; Skalidis, Raphael; Vervelaki, Anna; Masiero, Joseph R.; Mawet, Dimitri; Millar-Blanchaer, Maxwell A.; Panopoulou, Georgia, V; Tinyanont, Samaporn; Berdyugin, Andrei, V; Kagitani, Masato; Kravtsov, Vadim; Sakanoi, Takeshi; Imazawa, Ryo; Sasada, Mahito; Fukazawa, Yasushi; Kawabata, Koji S.; Uemura, Makoto; Mizuno, Tsunefumi; Nakaoka, Tatsuya; Akitaya, Hiroshi; Gurwell, Mark; Rao, Ramprasad; Di Lalla, Niccolo; Cibrario, Nicolo; Donnarumma, Immacolata; Kim, Dawoon E.; Omodei, Nicola; Pacciani, Luigi; Poutanen, Juri; Tavecchio, Fabrizio; Antonelli, Lucio A.; Bachetti, Matteo; Baldini, Luca; Baumgartner, Wayne H.; Bellazzini, Ronaldo; Bianchi, Stefano; Bongiorno, Stephen D.; Bonino, Raffaella; Brez, Alessandro; Bucciantini, Niccolo; Capitanio, Fiamma; Castellano, Simone; Ciprini, Stefano; Costa, Enrico; De Rosa, Alessandra; Del Monte, Ettore; Di Marco, Alessandro; Doroshenko, Victor; Dovciak, Michal; Enoto, Teruaki; Evangelista, Yuri; Fabiani, Sergio; Ferrazzoli, Riccardo; Garcia, Javier A.; Gunji, Shuichi; Hayashida, Kiyoshi; Heyl, Jeremy; Iwakiri, Wataru; Karas, Vladimir; Kitaguchi, Takao; Kolodziejczak, Jeffery J.; Krawczynski, Henric; La Monaca, Fabio; Latronico, Luca; Maldera, Simone; Manfreda, Alberto; Marin, Frederic; Marinucci, Andrea; Massaro, Francesco; Matt, Giorgio; Mitsuishi, Ikuyuki; Ng, C-Y; O'Dell, Stephen L.; Oppedisano, Chiara; Papitto, Alessandro; Pavlov, George G.; Peirson, Abel L.; Pesce-Rollins, Melissa; Petrucci, Pierre-Olivier; Pilia, Maura; Possenti, Andrea; Ramsey, Brian D.; Rankin, John; Ratheesh, Ajay; Romani, Roger W.; Sgro, Carmelo; Slane, Patrick; Soffitta, Paolo; Spandre, Gloria; Tamagawa, Toru; Taverna, Roberto; Tawara, Yuzuru; Tennant, Allyn F.; Thomas, Nicholas E.; Tombesi, Francesco; Trois, Alessio; Tsygankov, Sergey; Turolla, Roberto; Vink, Jacco; Weisskopf, Martin C.; Wu, Kinwah; Xie, Fei; Zane, Silvia.--This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Blazars are a class of jet-dominated active galactic nuclei with a typical double-humped spectral energy distribution. It is of common consensus that the synchrotron emission is responsible for the low frequency peak, while the origin of the high frequency hump is still debated. The analysis of X-rays and their polarization can provide a valuable tool to understand the physical mechanisms responsible for the origin of high-energy emission of blazars. We report the first observations of BL Lacertae (BL Lac) performed with the Imaging X-ray Polarimetry Explorer, from which an upper limit to the polarization degree ΠX < 12.6% was found in the 2–8 keV band. We contemporaneously measured the polarization in radio, infrared, and optical wavelengths. Our multiwavelength polarization analysis disfavors a significant contribution of proton-synchrotron radiation to the X-ray emission at these epochs. Instead, it supports a leptonic origin for the X-ray emission in BL Lac. © 2022. The Author(s). Published by the American Astronomical Society.The Imaging X-ray Polarimetry Explorer (IXPE) is a joint US and Italian mission. The US contribution is supported by the National Aeronautics and Space Administration (NASA) and led and managed by its Marshall Space Flight Center (MSFC), with industry partner Ball Aerospace (contract NNM15AA18C). The Italian contribution is supported by the Italian Space Agency (Agenzia Spaziale Italiana, ASI) through contract ASI-OHBI-2017-12-I.0, agreements ASI-INAF-2017-12-H0 and ASI-INFN-2017.13-H0, and its Space Science Data Center (SSDC), and by the Istituto Nazionale di Astrofisica (INAF) and the Istituto Nazionale di Fisica Nucleare (INFN) in Italy. This research used data products provided by the IXPE Team (MSFC, SSDC, INAF, and INFN) and distributed with additional software tools by the High-Energy Astrophysics Science Archive Research Center (HEASARC), at NASA Goddard Space Flight Center (GSFC). We acknowledge financial support from ASI-INAF agreement n. 2022-14-HH.0. The research at Boston University was supported in part by National Science Foundation grant AST-2108622 and NASA Swift Guest Investigator grant 80NSSC22K0537. This research has made use of data from the RoboPol program, a collaboration between Caltech, the University of Crete, IA-FORTH, IUCAA, the MPIfR, and the Nicolaus Copernicus University, which was conducted at Skinakas Observatory in Crete, Greece. The IAA-CSIC coauthors acknowledge financial support from the Spanish "Ministerio de Ciencia e Innovacion" (MCINN) through the "Center of Excellence Severo Ochoa" award for the Instituto de Astrofísica de Andalucía-CSIC (SEV-2017-0709). Acquisition and reduction of the POLAMI, TOP-MAPCAR, and OSN data was supported in part by MICINN through grants AYA2016-80889-P and PID2019-107847RB-C44. The POLAMI observations were carried out at the IRAM 30 m Telescope. IRAM is supported by INSU/CNRS (France), MPG (Germany), and IGN (Spain). This Letter makes use of the following ALMA director's discretionary time data under proposal ESO#2021.A.00016.T. ALMA is a partnership of ESO (representing its member states), NSF (USA), and NINS (Japan), together with NRC (Canada), MOST, and ASIAA (Taiwan), and KASI (Republic of Korea), in cooperation with the Republic of Chile. The Joint ALMA Observatory is operated by ESO, AUI/NRAO, and NAOJ. Some of the data reported here are based on observations obtained at the Hale Telescope, Palomar Observatory as part of a continuing collaboration between the California Institute of Technology, NASA/JPL, Yale University, and the National Astronomical Observatories of China. This research made use of Photutils, an Astropy package for detection and photometry of astronomical sources (Bradley et al. 2019). G.V.P. acknowledges support by NASA through the NASA Hubble Fellowship grant #HST-HF2-51444.001-A awarded by the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS5-26555. The data in this study include observations made with the Nordic Optical Telescope, owned in collaboration by the University of Turku and Aarhus University, and operated jointly by Aarhus University, the University of Turku, and the University of Oslo, representing Denmark, Finland, and Norway, the University of Iceland and Stockholm University at the Observatorio del Roque de los Muchachos, La Palma, Spain, of the Instituto de Astrofisica de Canarias. The data presented here were obtained in part with ALFOSC, which is provided by the Instituto de Astrofísica de Andalucía (IAA) under a joint agreement with the University of Copenhagen and NOT. E.L. was supported by Academy of Finland projects 317636 and 320045. Part of the French contribution is supported by the Scientific Research National Center (CNRS) and the French Spatial Agency (CNES). Some of the data are based on observations collected at the Observatorio de Sierra Nevada, owned and operated by the Instituto de Astrofísica de Andalucía (IAA-CSIC). Further data are based on observations collected at the Centro Astronómico Hispano-Alemán (CAHA), operated jointly by Junta de Andalucía and Consejo Superior de Investigaciones Científicas (IAA-CSIC). D.B., S.K., R.S., and N. M. acknowledge support from the European Research Council (ERC) under the European Unions Horizon 2020 research and innovation program under grant agreement No. 771282. C.C. acknowledges support by the European Research Council (ERC) under the HORIZON ERC Grants 2021 program under grant agreement No. 101040021. The Dipol-2 polarimeter was built in cooperation by the University of Turku, Finland, and the Leibniz Institut für Sonnenphysik, Germany, with support from the Leibniz Association grant SAW-2011-KIS-7. We are grateful to the Institute for Astronomy, University of Hawaii, for the allocated observing time. A.H. acknowledges The National Radio Astronomy Observatory is a facility of the National Science Foundation operated under cooperative agreement by Associated Universities, Inc. This work was supported by JST, the establishment of university fellowships toward the creation of science technology innovation; grant No. JPMJFS2129. This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI grant Nos. JP21H01137. This work was also partially supported by Optical and Near-Infrared Astronomy Inter-University Cooperation Program from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX2021-001131-S).Peer reviewe

A Model of Ischemia-Induced Neuroblast Activation in the Adult Subventricular Zone

We have developed a rat brain organotypic culture model, in which tissue slices contain cortex-subventricular zone-striatum regions, to model neuroblast activity in response to in vitro ischemia. Neuroblast activation has been described in terms of two main parameters, proliferation and migration from the subventricular zone into the injured cortex. We observed distinct phases of neuroblast activation as is known to occur after in vivo ischemia. Thus, immediately after oxygen/glucose deprivation (6–24 hours), neuroblasts reduce their proliferative and migratory activity, whereas, at longer time points after the insult (2 to 5 days), they start to proliferate and migrate into the damaged cortex. Antagonism of ionotropic receptors for extracellular ATP during and after the insult unmasks an early activation of neuroblasts in the subventricular zone, which responded with a rapid and intense migration of neuroblasts into the damaged cortex (within 24 hours). The process is further enhanced by elevating the production of the chemoattractant SDf-1α and may also be boosted by blocking the activation of microglia. This organotypic model which we have developed is an excellent in vitro system to study neurogenesis after ischemia and other neurodegenerative diseases. Its application has revealed a SOS response to oxygen/glucose deprivation, which is inhibited by unfavorable conditions due to the ischemic environment. Finally, experimental quantifications have allowed us to elaborate a mathematical model to describe neuroblast activation and to develop a computer simulation which should have promising applications for the screening of drug candidates for novel therapies of ischemia-related pathologies

Nuclear ERK1/2 signaling potentiation enhances neuroprotection and cognition via Importinα1/KPNA2

Cell signaling is central to neuronal activity and its dysregulation may lead to neurodegeneration and cognitive decline. Here, we show that selective genetic potentiation of neuronal ERK signaling prevents cell death in vitro and in vivo in the mouse brain, while attenuation of ERK signaling does the opposite. This neuroprotective effect mediated by an enhanced nuclear ERK activity can also be induced by the novel cell penetrating peptide RB5. In vitro administration of RB5 disrupts the preferential interaction of ERK1 MAP kinase with importinα1/KPNA2 over ERK2, facilitates ERK1/2 nuclear translocation, and enhances global ERK activity. Importantly, RB5 treatment in vivo promotes neuroprotection in mouse models of Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) disease, and enhances ERK signaling in a human cellular model of HD. Additionally, RB5‐mediated potentiation of ERK nuclear signaling facilitates synaptic plasticity, enhances cognition in healthy rodents, and rescues cognitive impairments in AD and HD models. The reported molecular mechanism shared across multiple neurodegenerative disorders reveals a potential new therapeutic target approach based on the modulation of KPNA2‐ERK1/2 interactions

The Polarized Cosmic Hand: IXPE Observations of PSR B1509-58/MSH 15-52

We describe IXPE polarization observations of the Pulsar Wind Nebula (PWN) MSH15-52, the `Cosmic Hand'. We find X-ray polarization across the PWN, with B field vectors generally aligned with filamentary X-ray structures. High significance polarization is seen in arcs surrounding the pulsar and toward the end of the `jet', with polarization degree PD>70%, thus approaching the maximum allowed synchrotron value. In contrast, the base of the jet has lower polarization, indicating a complex magnetic field at significant angle to the jet axis. We also detect significant polarization from PSR B1509-58 itself. Although only the central pulse-phase bin of the pulse has high individual significance, flanking bins provide lower significance detections and, in conjunction with the X-ray image and radio polarization, can be used to constrain rotating vector model solutions for the pulsar geometry.Comment: To appear in the Astrophysical Journa

The IXPE View of GRB 221009A

We present the IXPE observation of GRB 221009A, which includes upper limits on the linear polarization degree of both prompt and afterglow emission in the soft X-ray energy band. GRB 221009A is an exceptionally bright gamma-ray burst (GRB) that reached Earth on 2022 October 9 after traveling through the dust of the Milky Way. The Imaging X-ray Polarimetry Explorer (IXPE) pointed at GRB 221009A on October 11 to observe, for the first time, the 2–8 keV X-ray polarization of a GRB afterglow. We set an upper limit to the polarization degree of the afterglow emission of 13.8% at a 99% confidence level. This result provides constraints on the jet opening angle and the viewing angle of the GRB, or alternatively, other properties of the emission region. Additionally, IXPE captured halo-rings of dust-scattered photons that are echoes of the GRB prompt emission. The 99% confidence level upper limit to the prompt polarization degree depends on the background model assumption, and it ranges between ∼55% and ∼82%. This single IXPE pointing provides both the first assessment of X-ray polarization of a GRB afterglow and the first GRB study with polarization observations of both the prompt and afterglow phases

First detection of X-ray polarization from the accreting neutron star 4U 1820-303

This paper reports the first detection of polarization in the X-rays for atoll-source 4U 1820-303, obtained with the Imaging X-ray Polarimetry Explorer (IXPE) at 99.999% confidence level (CL). Simultaneous polarimetric measurements were also performed in the radio with the Australia Telescope Compact Array (ATCA). The IXPE observations of 4U 1820-303 were coordinated with Swift-XRT, NICER, and NuSTAR aiming to obtain an accurate X-ray spectral model covering a broad energy interval. The source shows a significant polarization above 4 keV, with a polarization degree of 2.0(0.5)% and a polarization angle of -55(7) deg in the 4-7 keV energy range, and a polarization degree of 10(2)% and a polarization angle of -67(7) deg in the 7-8 keV energy bin. This polarization also shows a clear energy trend with polarization degree increasing with energy and a hint for a position-angle change of about 90 deg at 96% CL around 4 keV. The spectro-polarimetric fit indicates that the accretion disk is polarized orthogonally to the hard spectral component, which is presumably produced in the boundary/spreading layer. We do not detect linear polarization from the radio counterpart, with a 99.97% upper limit of 50% at 7.25 GHz

Polarized blazar X-rays imply particle acceleration in shocks

Most of the light from blazars, active galactic nuclei with jets of magnetized plasma that point nearly along the line of sight, is produced by high-energy particles, up to around 1 TeV. Although the jets are known to be ultimately powered by a supermassive black hole, how the particles are accelerated to such high energies has been an unanswered question. The process must be related to the magnetic field, which can be probed by observations of the polarization of light from the jets. Measurements of the radio to optical polarization—the only range available until now—probe extended regions of the jet containing particles that left the acceleration site days to years earlier1,2,3, and hence do not directly explore the acceleration mechanism, as could X-ray measurements. Here we report the detection of X-ray polarization from the blazar Markarian 501 (Mrk 501). We measure an X-ray linear polarization degree ΠX of around 10%, which is a factor of around 2 higher than the value at optical wavelengths, with a polarization angle parallel to the radio jet. This points to a shock front as the source of particle acceleration and also implies that the plasma becomes increasingly turbulent with distance from the shock