Neuroscience
- Somatodendritic accumulation of Tau in Alzheimer's disease is promoted by Fyn‐mediated local protein translation
- 1Clem Jones Centre for Ageing Dementia Research (CJCADR), Queensland Brain Institute (QBI), The University of Queensland, Brisbane, Qld, Australia
- ↵*Corresponding author. Tel: +61 7 334 66329; E‐mail: j.goetz{at}uq.edu.au
Aggregation of hyper‐phosphorylated Tau in the somatodendritic domain, as often seen in Alzheimer's disease, is caused by local translation triggered by the presence of amyloid‐β.
Synopsis
Amyloid‐β (Aβ) promotes de novo protein synthesis of Tau and its hyperphosphorylation in the somatodendritic domain, in a process mediated by Fyn kinase‐dependent activation of ERK/S6 signaling. This finding presents a novel mechanism for somatodendritic Tau accumulation and aggregation in disease.
Fyn kinase boosts Tau translation and phosphorylation.
Aβ promotes translation of axonally enriched Tau in the somatodendritic domain.
Aβ activates the ERK/S6 pathway via Fyn to induce Tau translation.
Tau accumulates in Aβ‐depositing, Aβ‐injected and Fyn‐overexpressing brains.
Fyn activity is required for Aβ‐induced Tau synthesis.
The EMBO Journal (2017) 36: 3120–3138
- Received July 5, 2017.
- Revision received July 25, 2017.
- Accepted August 10, 2017.
- © 2017 The Authors
- Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity
- Zachary Monahan1,†,
- Veronica H Ryan2,†,
- Abigail M Janke3,
- Kathleen A Burke3,
- Shannon N Rhoads1,
- Gül H Zerze4,
- Robert O'Meally5,
- Gregory L Dignon4,
- Alexander E Conicella6,
- Wenwei Zheng7,
- Robert B Best7,
- Robert N Cole5,
- Jeetain Mittal4,
- Frank Shewmaker (fshewmaker{at}usuhs.edu)*,1 and
- Nicolas L Fawzi (nicolas_fawzi{at}brown.edu)*,2,3,6
- 1Department of Pharmacology and Molecular Therapeutics, Uniformed Services University, Bethesda, MD, USA
- 2Neuroscience Graduate Program, Brown University, Providence, RI, USA
- 3Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI, USA
- 4Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, PA, USA
- 5Johns Hopkins Mass Spectrometry and Proteomic Facility, Johns Hopkins University, Baltimore, MD, USA
- 6Graduate Program in Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA
- 7Laboratory of Chemical Physics, National Institutes of Health, Bethesda, MD, USA
- ↵*
Corresponding author. Tel: +1 301 295 3527; E‐mail: fshewmaker{at}usuhs.edu
Corresponding author. Tel: +1 401 863 5232; E‐mail: nicolas_fawzi{at}brown.edu
↵† These authors contributed equally to this work
Post‐translational modification emerges as a cellular mechanism for controlling physiological assembly of the ALS and FTD neurodegenerative disease‐linked RNA‐binding protein FUS.
Synopsis
Self‐association of the ALS and FTD neurodegenerative disease‐linked RNA‐binding protein FUS is regulated by phosphorylation of its low complexity domain.
FUS low complexity (LC) domain can be phosphorylated at several sites: by DNA‐PK at 12 sites in vitro, and in human cells after DNA damage at additional sites.
FUS LC phosphorylation and phosphomimetic substitution discourages phase separation and aggregation.
FUS LC phosphomimetic substitution decreases FUS aggregation in yeast and human cell models.
FUS LC phosphomimetic substitution reduces FUS toxicity in the yeast model.
The EMBO Journal (2017) 36: 2951–2967
- Received December 23, 2016.
- Revision received July 6, 2017.
- Accepted July 7, 2017.
- © 2017 The Authors. Published under the terms of the CC BY NC ND 4.0 license
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
- Heteromeric channels formed by TRPC1, TRPC4 and TRPC5 define hippocampal synaptic transmission and working memory
- Jenny Bröker‐Lai1,
- Astrid Kollewe2,†,
- Barbara Schindeldecker3,†,
- Jörg Pohle1,4,†,
- Vivan Nguyen Chi5,†,
- Ilka Mathar1,
- Raul Guzman3,
- Yvonne Schwarz3,
- Alan Lai1,
- Petra Weißgerber6,
- Herbert Schwegler7,
- Alexander Dietrich8,
- Martin Both5,
- Rolf Sprengel9,
- Andreas Draguhn5,
- Georg Köhr4,
- Bernd Fakler2,10,
- Veit Flockerzi6,
- Dieter Bruns3 and
- Marc Freichel (marc.freichel{at}pharma.uni-heidelberg.de)*,1
- 1Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
- 2Institute of Physiology, University of Freiburg, Freiburg, Germany
- 3Center for Integrative Physiology and Molecular Medicine, Saarland University, Homburg, Germany
- 4Physiology of Neural Networks, Psychiatry/Psychopharmacology, Central Institute of Mental Health, J5, Heidelberg University, Mannheim, Germany
- 5Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
- 6Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany
- 7Institute of Anatomy, University of Magdeburg, Magdeburg, Germany
- 8Walther‐Straub‐Institute for Pharmacology and Toxicology, Ludwig‐Maximilians‐University München, München, Germany
- 9Max Planck Research Group of the Max Planck Institute for Medical Research at the Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany
- 10BIOSS, Center for Biological Signaling Studies, University of Freiburg, Freiburg, Germany‡
- ↵*Corresponding author. Tel: +49 6221 54 86861; E‐mail: marc.freichel{at}pharma.uni-heidelberg.de
↵† These authors contributed equally to this work
Spatial working memory and flexible relearning requires the formation and function of hetero‐multimeric complexes of specific TRP channels in the mouse brain.
Synopsis
Heteromers from TRPC1, TRPC4 and TRPC5 define hippocampal synaptic transmission and specific mnemonic behavior.
TRPC1, TRPC4, and TRPC5 assemble into heteromultimers with each other, but not with other TRP family members in the mouse brain and hippocampus.
TRPC1/4/5 deficiency reduced action potential evoked responses in vitro and in situ, but LTP and depotentiation remained unchanged.
In Trpc1/4/5 triple knockout mice cross‐frequency phase‐amplitude coupling is impaired while basal neuronal network oscillations are unchanged.
Trpc1/4/5 triple knock out mice display deficits in spatial working memory and when adapting to a new challenge in a re‐learning task, whereas the acquisition of spatial reference memory remains unaltered.
The EMBO Journal (2017) 36: 2770–2789
- Received December 22, 2016.
- Revision received July 1, 2017.
- Accepted July 7, 2017.
- © 2017 The Authors
- Formin 2 links neuropsychiatric phenotypes at young age to an increased risk for dementia
- Roberto Carlos Agís‐Balboa1,13,
- Paulo S Pinheiro2,3,5,14,†[Link],
- Nelson Rebola2,3,14,†[Link],
- Cemil Kerimoglu1,4,
- Eva Benito1,
- Michael Gertig1,
- Sanaz Bahari‐Javan4,
- Gaurav Jain1,
- Susanne Burkhardt1,
- Ivana Delalle5,
- Alexander Jatzko6,
- Markus Dettenhofer7,
- Patricia A Zunszain8,
- Andrea Schmitt9,10,
- Peter Falkai9,
- Julius C Pape11,
- Elisabeth B Binder11,
- Christophe Mulle2,3,
- Andre Fischer (andre.fischer{at}dzne.de)*,1,4 and
- Farahnaz Sananbenesi (farahnaz.sananbenesi{at}dzne.de)*,1,12
- 1Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Göttingen, Göttingen, Germany
- 2Interdisciplinary Institute for Neuroscience, University of Bordeaux, Bordeaux, France
- 3CNRS UMR 5297, Bordeaux, France
- 4Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany
- 5Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA
- 6Department of Psychosomatics, Westpfalzklinikum‐Kaiserslautern, Teaching Hospital, University of Mainz, Mainz, Germany
- 7CEITEC – Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- 8Stress, Psychiatry and Immunology Laboratory, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
- 9Department of Psychiatry and Psychotherapy, LMU Munich, Munich, Germany
- 10Laboratory of Neuroscience (LIM27), Institute of Psychiatry, University of Sao Paulo, São Paulo, Brazil
- 11Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
- 12Research Group for Genome Dynamics in Brain Diseases, Göttingen, Germany
- 13Present Address: Psychiatric Diseases Research Group, Galicia Sur Health Research Institute, Sergas, Cibersam, Complexo Hospitalario Universitario de Vigo (CHUVI), Vigo, Spain
- 14Present Address: CNC‐Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- ↵*
Corresponding author. Tel: +49 551 3961211; E‐mail: andre.fischer{at}dzne.de
Corresponding author. Tel: +49 551 39 61211; Fax: +49 3961212; E‐mail: farahnaz.sananbenesi{at}dzne.de
↵† These authors contributed equally to this work
Deregulation of the actin cytoskeleton regulator Formin 2 is a common denominator of post‐traumatic stress disorders and age‐dependent Alzheimer's disease phenotypes, possibly explaining their clinical connection.
Synopsis
People suffering from post‐traumatic stress disorder at a young age have an increased risk to develop Alzheimer's disease. The actin nucleator Formin 2 and altered transcriptional homeostasis play a key role in this.
Loss of FMN2 causes PTSD‐like phenotypes in young mice.
Loss of FMN2 leads to accelerated age‐associated memory decline.
Age‐associated memory decline in FMN2 mutant mice is linked to aberrant gene expression.
HDAC inhibition reinstates memory function in aged FMN2 mutant mice.
The EMBO Journal (2017) 36: 2815–2828
- Received February 25, 2017.
- Revision received June 23, 2017.
- Accepted June 27, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- APP mouse models for Alzheimer's disease preclinical studies
- Hiroki Sasaguri (hiroki.sasaguri{at}riken.jp)*,1,2,
- Per Nilsson1,3,
- Shoko Hashimoto1,
- Kenichi Nagata1,
- Takashi Saito1,4,
- Bart De Strooper5,6,7,
- John Hardy8,
- Robert Vassar9,
- Bengt Winblad3 and
- Takaomi C Saido (saido{at}brain.riken.jp)*,1
- 1Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako, Japan
- 2Department of Neurology and Neurological Science, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
- 3Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden
- 4Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
- 5Dementia Research Institute, University College London, London, UK
- 6Department for Neurosciences, KU Leuven, Leuven, Belgium
- 7VIB Center for Brain and Disease Research, Leuven, Belgium
- 8Reta Lila Research Laboratories and the Department of Molecular Neuroscience, University College London Institute of Neurology, London, UK
- 9Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- ↵*
Corresponding author. Tel: +81 48 4621111 (ext 7613); E‐mail: hiroki.sasaguri{at}riken.jp
Corresponding author. Tel: +81 48 4679715; E‐mail: saido{at}brain.riken.jp
Outlining the historical progression of preclinical Alzheimer's disease models, this review compares the respective strengths and limitations of different transgenic models expressing mutant amyloid precursor protein (APP).
The EMBO Journal (2017) 36: 2473–2487
- Received May 19, 2017.
- Revision received June 9, 2017.
- Accepted July 7, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Epigenome profiling and editing of neocortical progenitor cells during development
- Mareike Albert (albert{at}mpi-cbg.de)*,1,
- Nereo Kalebic1,
- Marta Florio1,2,
- Naharajan Lakshmanaperumal1,
- Christiane Haffner1,
- Holger Brandl1,
- Ian Henry1 and
- Wieland B Huttner (huttner{at}mpi-cbg.de)*,1
- 1Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
- 2Present Address: Department of Genetics, Harvard Medical School, Boston, MA, USA
- ↵*
Corresponding author. Tel: +49 3512102417; E‐mail: albert{at}mpi-cbg.de
Corresponding author. Tel: +49 3512101500; E‐mail: huttner{at}mpi-cbg.de
Mapping genome‐wide histone methylation in distinct mouse neural cell types reveals major changes associated with brain development, while genome editing shows how transient changes in chromatin status can affect regulation of specific genes.
Synopsis
Epigenome maps for distinct neural cell populations in the developing mouse neocortex reveal extensive H3K4me3 and H3K27me3 changes. Editing at the gene encoding transcription factor Eomes suggests that dynamic H3K27me3 changes are required for normal neocortex development.
Genome‐wide histone methylation maps with cell type‐resolution identifies potential new regulators in the developing mouse neocortex.
Dynamic H3K27me3 changes on promoters of several key neural transcription factors coincide with cell fate transitions.
Ezh2 targeting via catalytically inactivate Cas9 enables editing of H3K27me3 in vivo in the developing neocortex.
Forced H3K27me3 deposition at the Eomes locus reduces expression of this transcription factor, affecting basal progenitor abundance.
The EMBO Journal (2017) 36: 2642–2658
- Received February 17, 2017.
- Revision received June 27, 2017.
- Accepted July 3, 2017.
- © 2017 The Authors
- OH MYeloid! Immune cells wreaking havoc on brain homeostasis
- 1Stanford Neurosciences Graduate Training Program, Stanford University School of Medicine, Stanford, CA, USA
- 2Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- 3Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Healthcare System, Palo Alto, CA, USA
- 4Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA
Genetic mutations responsible for neurodegenerative Nasu‐Hakola disease have been localized to the gene TREM2 and its adaptor DAP12, but it remained unclear what causes the brain to deteriorate. In this issue of The EMBO Journal, Kleinberger et al (2017) provide intriguing evidence suggesting a TREM2 mutation alone can lead to striking microglial dysfunction and precipitate changes in cerebral blood flow and metabolism in mice.
See also: G Kleinberger et al (July 2017)
New mouse models show that dementia‐associated TREM2 mutation can cause microglial dysfunction and precipitate changes in cerebral blood flow and metabolism.
- © 2017 The Authors
- The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism
- Gernot Kleinberger1,2,
- Matthias Brendel3,
- Eva Mracsko4,
- Benedikt Wefers5,6,
- Linda Groeneweg4,
- Xianyuan Xiang1,
- Carola Focke3,
- Maximilian Deußing3,
- Marc Suárez‐Calvet1,5,
- Fargol Mazaheri5,
- Samira Parhizkar1,
- Nadine Pettkus1,
- Wolfgang Wurst2,5,6,7,
- Regina Feederle2,5,8,
- Peter Bartenstein2,3,
- Thomas Mueggler4,
- Thomas Arzberger5,9,10,
- Irene Knuesel4,
- Axel Rominger2,3 and
- Christian Haass (christian.haass{at}mail03.med.uni-muenchen.de)*,1,2,5
- 1Biomedical Center (BMC), Biochemistry, Ludwig‐Maximilians‐Universität München, Munich, Germany
- 2Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
- 3Department of Nuclear Medicine, Ludwig‐Maximilians‐Universität München, Munich, Germany
- 4NORD Discovery & Translational Area, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
- 5German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
- 6Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- 7Technische Universität München, Freising‐Weihenstephan, Germany
- 8Helmholtz Center Munich, German Research Center for Environmental Health, Institute for Diabetes and Obesity, Core Facility Monoclonal Antibody Development, Munich, Germany
- 9Center for Neuropathology and Prion Research, Ludwig‐Maximilians‐Universität München, Munich, Germany
- 10Department of Psychiatry and Psychotherapy, Ludwig‐Maximilians‐Universität München, Munich, Germany
- ↵*Corresponding author. Tel: +49 89 4400 46549; E‐mail: christian.haass{at}mail03.med.uni-muenchen.de
A knock‐in mouse model of the frontotemporal dementia disease‐associated TREM2 mutation, p.T66M, shows a loss‐of‐function phenotype with age‐dependent reduction in microglial activity and systemic metabolic alterations throughout the brain.
Synopsis
Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia (FTD). Homozygous endogenous expression of the TREM2 p.T66M mutation impairs microglia function, brain perfusion and glucose metabolism, suggesting that microglial TREM2 acts as a signaling hub.
Trem2 p.T66M knock‐in mice show delayed resolution of inflammation.
Trem2 p.T66M knock‐in mice exhibit decreased age‐dependent microglial activity.
Trem2 p.T66M knock‐in mice show reduced cerebral blood flow.
Trem2 p.T66M knock‐in mice show reduced glucose metabolism.
The EMBO Journal (2017) 36: 1837–1853
- Received January 12, 2017.
- Revision received April 21, 2017.
- Accepted April 27, 2017.
- © 2017 The Authors
- PAR‐1 promotes microtubule breakdown during dendrite pruning in Drosophila
- Svende Herzmann1,
- Rafael Krumkamp1,
- Sandra Rode1,
- Carina Kintrup1 and
- Sebastian Rumpf (sebastian.rumpf{at}uni-muenster.de)*,1
- ↵*Corresponding author. Tel: +49 251 8322390; E‐mail: sebastian.rumpf{at}uni-muenster.de
Severing of unspecific neurites during neuronal morphogenesis is facilitated by PAR‐1‐mediated Tau phosphorylation, which increases microtubule dynamics prior to disassembly.
Synopsis
The developmental elimination of long stretches of neurite during neuronal morphogenesis—also known as pruning—involves the disassembly of microtubules in affected neurites. Using genetic and imaging analyses of dendrite pruning in Drosophila, we found that microtubule disruption is driven by the kinase PAR‐1, likely via an inhibitory effect on Tau.
Mutation or knockdown of PAR‐1 leads to dendrite pruning defects.
Loss of PAR‐1 prevents microtubule disruption during pruning.
PAR‐1 increases microtubule dynamics at the onset of pruning.
Genetic analysis suggests Tau is the relevant PAR‐1 target.
PAR‐1 is also required for subsequent membrane collapse.
The EMBO Journal (2017) 36: 1981–1991
- Received October 15, 2016.
- Revision received April 21, 2017.
- Accepted April 26, 2017.
- © 2017 The Authors
- Is magnetogenetics the new optogenetics?
Optogenetics has revolutionised neuroscience as it enables investigators to establish causal relationships between neuronal activity and a behavioural outcome in a temporally precise manner. It is a powerful technology, but limited by the necessity to deliver light to the cells of interest, which often requires invasive surgery and a tethered light source. Magnetogenetics aims to overcome these issues by manipulating neurons with magnetic stimuli. As magnetic fields can pass freely through organic tissue, it requires no surgery or tethering the animals to an energy source. In this commentary, we assess the utility of magnetogenetics based on three different approaches: magneto‐thermo‐genetics; force/torque‐based methods; and expression of the iron chaperone ISCA1. Despite some progress, many hurdles need to be overcome if magnetogenetics is to take the helm from optogenetics.
The technology has great potential as a tool for precise and efficient activation of neurons in any species without the need for invasive surgery but many technical and biological hurdles still stand in the way of application.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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