Neuroscience
- Messages from forgotten friends: classic cell adhesion molecules inhibit regeneration too
A necessary step toward complete functional recovery after spinal cord injury is the regeneration of axons. Axon regrowth after injury is prevented by a myriad of intrinsic and extrinsic factors. In this issue of The EMBO Journal, Huang et al (2016) demonstrate that the cell adhesion molecule NB‐3 (CNTN6) functions as a major brake on axon regrowth when it is activated by NB‐3 from scar‐forming cells at the injury site. Disruption of this NB‐3 trans‐cellular signaling led to impressive axon regrowth after spinal cord transection.
See also: Z Huang et al (August 2016)
Trans‐cellular signaling between neurons and scar‐forming cells mediated by the adhesion molecule NB‐3 constitutes one of the brakes that inhibits axon regeneration following spinal cord injury.
- © 2016 The Authors
- Droplet organelles?
- ↵*Corresponding author. Tel: +1 203 785 3322; E‐mail: karla.neugebauer{at}yale.edu
Non‐membrane‐bound cellular structures such as nucleoli, stress granules, Cajal and P bodies have been long established. Recent data reviewed by Neugebauer and colleagues delineate liquid–liquid phase separation processes that underlie the dynamic nature of these organelles composed of low‐complexity proteins and RNA.
The EMBO Journal (2016) 35: 1603–1612
- Received November 18, 2015.
- Revision received March 1, 2016.
- Accepted June 3, 2016.
- © 2016 The Authors
- A PBX1 transcriptional network controls dopaminergic neuron development and is impaired in Parkinson's disease
- J Carlos Villaescusa1,2,3,
- Bingsi Li4,
- Enrique M Toledo1,
- Pia Rivetti di Val Cervo1,
- Shanzheng Yang1,
- Simon RW Stott5,
- Karol Kaiser1,2,
- Saiful Islam1,8,
- Daniel Gyllborg1,
- Rocio Laguna‐Goya5,
- Michael Landreh6,9,
- Peter Lönnerberg1,
- Anna Falk7,
- Tomas Bergman6,
- Roger A Barker5,
- Sten Linnarsson1,
- Licia Selleri4 and
- Ernest Arenas (ernest.arenas{at}ki.se)*,1
- 1Laboratory of Molecular Neurobiology, DBRM, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
- 2Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
- 3Psychiatric Stem Cell Group, Neurogenetics Unit, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
- 4Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY, USA
- 5John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK
- 6Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics Karolinska Institutet, Stockholm, Sweden
- 7Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
- 8Genetics Department, Stanford University, Stanford, CA, USA
- 9 Department of Chemistry, Physical & Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford, UK
- ↵*Corresponding author. Tel: +46 852487663; Fax: +46 8341960; E‐mail: ernest.arenas{at}ki.se
The homeobox factor PBX1 directly represses or activates key genes involved in specification, survival, and oxidative stress protection of midbrain dopaminergic neurons.
Synopsis
PBX1 controls a novel transcriptional network required for midbrain dopaminergic specification and survival. PBX1 and its target NFE2L1 protect dopaminergic neurons from oxidative stress, and their levels are severely reduced in the substantia nigra of Parkinson's disease patients.
Pbx1 is expressed in a subpopulation of dopaminergic neuroblasts and controls the specification and survival of midbrain dopaminergic neurons.
PBX1 plays a dual role in transcription by directly repressing or activating genes, such as Onecut2 to inhibit lateral fates during embryogenesis, Pitx3 to promote mDAn development, and Nfe2l1 to protect from oxidative stress.
PBX1 and NFE2L1 protect dopaminergic neurons from oxidative stress.
Nuclear PBX1 and NFE2L1 levels are severely reduced in midbrain dopaminergic neurons of Parkinson's disease patients.
The EMBO Journal (2016) 35: 1963–1978
- Received December 16, 2015.
- Revision received June 1, 2016.
- Accepted June 3, 2016.
- © 2016 The Authors
- The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy
- Christopher P Webster1,†,
- Emma F Smith1,†,
- Claudia S Bauer1,
- Annekathrin Moller1,
- Guillaume M Hautbergue1,
- Laura Ferraiuolo1,
- Monika A Myszczynska1,
- Adrian Higginbottom1,
- Matthew J Walsh1,
- Alexander J Whitworth2,4,
- Brian K Kaspar3,
- Kathrin Meyer3,
- Pamela J Shaw1,
- Andrew J Grierson1,‡ and
- Kurt J De Vos*,1,‡
- 1Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience University of Sheffield, Sheffield, UK
- 2Department of Biomedical Science, University of Sheffield, Sheffield, UK
- 3The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
- 4MRC Mitochondrial Biology Unit, Cambridge, UK
- ↵*Corresponding author. Tel: +44 114 222 2241; E‐mail: k.de_vos{at}sheffield.ac.uk
ALS/FTD‐associated C9orf72 is a Rab1a effector that controls initiation of autophagy by regulating ULK1 complex trafficking.
Synopsis
C9ALS/FTD‐associated C9orf72 is a Rab1a effector that controls initiation of autophagy by regulating ULK1 complex trafficking. Disruption of C9orf72 function inhibits autophagy and mimics the p62 pathology found in C9ALS/FTD patients. C9ALS/FTD iNeurons display reduced autophagy.
C9orf72 regulates ULK1 complex‐dependent initiation of autophagy.
C9orf72 is a Rab1a effector that controls trafficking of the ULK1 complex.
C9orf72 deficiency inhibits autophagy and mimics C9ALS/FTD p62 pathology.
C9ALS/FTD patient‐derived iNeurons display reduced autophagy.
The EMBO Journal (2016) 35: 1656–1676
- Received March 22, 2016.
- Revision received June 2, 2016.
- Accepted June 3, 2016.
- © 2016 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.
- The minor spliceosome could be the major key for FUS/TLS mutants in ALS
- Emanuele Buratti (emanuele.buratti{at}icgeb.org)1
Despite its name, minor spliceosome alterations are often involved in human disease origin. Work by Reber et al (2016) in this issue of The EMBO Journal now demonstrates a connection between minor spliceosome components and FUS/TLS, one of the major proteins aggregating in the brain of patients affected by amyotrophic lateral sclerosis (ALS). This finding has important implications as it extends the spectrum of diseases where minor spliceosome plays a role. It may also represent a new opportunity for specific therapeutic targets.
See also: S Reber et al (July 2016)
The discovery that RNA‐binding protein FUS/TLS interacts with snRNP U11 and controls the splicing rate for minor introns offers a new basis for understanding the onset of amyotrophic lateral sclerosis.
- © 2016 The Author
- DnaJ/Hsc70 chaperone complexes control the extracellular release of neurodegenerative‐associated proteins
- Sarah N Fontaine*,1,2,†,
- Dali Zheng1,
- Jonathan J Sabbagh1,2,†,
- Mackenzie D Martin1,2,†,
- Dale Chaput3,
- April Darling1,
- Justin H Trotter4,
- Andrew R Stothert1,
- Bryce A Nordhues1,
- April Lussier1,
- Jeremy Baker1,
- Lindsey Shelton1,
- Mahnoor Kahn1,
- Laura J Blair1,
- Stanley M Stevens Jr3 and
- Chad A Dickey*,1,2,†
- 1Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA
- 2James A. Haley Veteran's Hospital, Tampa, FL, USA
- 3Department of Cell, Molecular and Life Sciences, University of South Florida, Tampa, FL, USA
- 4Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA
- ↵*
Corresponding author. Tel: +1 813 396 0670; E‐mail: sarah.fontaine{at}uky.edu
Corresponding author. Tel: +1 813 396 0639; E‐mail: cdickey{at}health.usf.edu
↵† This article has been contributed to by US Government employees and their work is in the public domain in the USA
DnaJC5 is a co‐chaperone for Hsc70 and SNARE‐dependent neuronal release of disease proteins such as tau, TDP‐43, or α‐synuclein.
Synopsis
The DnaJC5 protein, cysteine string protein‐α (CSPα), stimulates the release of neurodegenerative proteins through a non‐canonical exocytosis pathway.
Increased expression of DnaJC5 promotes extracellular release of the microtubule‐associated protein tau, α‐synuclein, and TAR‐DNA binding protein.
Release of these proteins is dependent upon both the SNARE, SNAP‐23, and the constitutively expressed Hsp70 variant, Hsc70.
This function of DnaJC5 and the Hsc70 complex is unique as other DnaJs and Hsp70 variants do not promote this mechanism.
This finding provides a mechanism for how aggregate‐prone proteins can exit the cell and possibly seed propagation.
The EMBO Journal (2016) 35: 1537–1549
- Received November 16, 2015.
- Revision received April 25, 2016.
- Accepted April 27, 2016.
- © 2016 The Authors
- Dopamine signaling promotes the xenobiotic stress response and protein homeostasis
- 1Department of Genetics, The Waksman Institute Rutgers The State University of New Jersey, Piscataway, NJ, USA
- ↵*Corresponding author. Tel: +1 848 445 0955; Fax: +1 732 445 5735; E‐mail: rongo{at}waksman.rutgers.edu
Dopaminergic sensory neuron signaling to epithelial cells promotes resistance to pathogenic bacteria and heat‐shock stress in nematodes.
Synopsis
Upon sensing bacteria, sensory neurons in the nematode C. elegans release the neurohormone dopamine, which acts through dopamine receptors on epithelial cells to promote the expression of xenobiotic stress response genes involved in pathogenic resistance and toxin removal. These genes in turn promote protein homeostasis and resistance to pathogenic infection.
Mechanosensory neurons release dopamine in response to viscous bacteria encountered in the environment.
Dopamine acts through D1‐type receptors on epithelial cells of the intestine and hypodermis to promote the expression of xenobiotic stress resistance genes, including multiple cytochrome P450 enzymes and glycosyl transferases.
In the absence of dopamine signaling or xenobiotic stress resistance gene activity, nematodes show signs of proteotoxic stress and susceptibility to infection.
The turnover of particularly unstable proteins is sensitive to this proteotoxic stress because the protein quality control mechanisms that normally remove such proteins become titrated away by larger proteome damage.
By promoting xenobiotic detoxification and protein homeostasis, dopamine signaling prepares frontline epithelia to defend against possible infection.
The EMBO Journal (2016) 35: 1885–1901
- Received July 10, 2015.
- Revision received April 14, 2016.
- Accepted May 3, 2016.
- © 2016 The Authors
- Minor intron splicing is regulated by FUS and affected by ALS‐associated FUS mutants
- Stefan Reber1,2,
- Jolanda Stettler1,6,
- Giuseppe Filosa3,4,
- Martino Colombo1,2,
- Daniel Jutzi1,
- Silvia C Lenzken3,
- Christoph Schweingruber1,2,
- Rémy Bruggmann5,
- Angela Bachi4,
- Silvia ML Barabino3,
- Oliver Mühlemann*,1 and
- Marc‐David Ruepp*,1
- 1Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland
- 2Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
- 3Department of Biotechnology and Biosciences, University of Milano‐Bicocca, Milan, Italy
- 4IFOM‐FIRC Institute of Molecular Oncology, Milan, Italy
- 5Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland
- 6Interregionale Blutspende SRK AG, Bern, Switzerland
- ↵*
Corresponding author. Tel: +41 31 631 4348; E‐mail: marc.ruepp{at}dcb.unibe.ch
Corresponding author. Tel: +41 31 631 4627; E‐mail: oliver.muehlemann{at}dcb.unibe.ch
The RNA‐binding protein FUS, frequently mutated in amyotrophic lateral sclerosis (ALS), binds to U11 snRNP and affects splicing of minor intron‐containing mRNAs that may contribute to ALS pathology.
Synopsis
Mutations in RNA‐binding protein FUS are frequently found in familial amyotrophic lateral sclerosis (ALS). This study shows FUS to control minor intron splicing via binding to the U11/12 snRNP and identifies target mRNAs that may contribute to disease pathology.
Fused in sarcoma (FUS) interacts with the minor spliceosome and affects minor intron splicing.
Loss of FUS results in a strong deregulation of minor intron‐containing genes.
FUS with an ALS‐associated mutation mislocalizes to the cytoplasm and inhibits minor intron splicing.
ALS‐associated cytoplasmic FUS sequesters U11 and U12 snRNA in cytoplasmic aggregates.
The EMBO Journal (2016) 35: 1504–1521
- Received December 31, 2015.
- Revision received April 28, 2016.
- Accepted April 29, 2016.
- © 2016 The Authors
- Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis
- Noemí Pallas‐Bazarra1,2,
- Jerónimo Jurado‐Arjona1,2,
- Marta Navarrete1,
- Jose A Esteban1,
- Félix Hernández1,3,
- Jesús Ávila*,1,2 and
- María Llorens‐Martín*,1,2
- 1Centro de Biología Molecular Severo Ochoa (CSIC‐UAM), Madrid, Spain
- 2Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain
- 3Sciences Faculty, Autonoma University, Madrid, Spain
- ↵*
Corresponding author. Tel: +34 91 196 45 92; Fax: +34 91 196 44 20; E‐mail: m.llorens{at}csic.es
Corresponding author. Tel: +34 196 45 64; Fax: +34 91 196 44 20; E‐mail: javila{at}cbm.csic.es
Tau protein plays an unexpected key role in the regulation of adult hippocampal neurogenesis, both under basal conditions and in response to stressing or enriching environmental settings.
Synopsis
Tau regulates the in vivo maturation of newborn granule neurons under physiological conditions. In addition, Tau deficiency prevents both the detrimental and stimulatory actions of acute stress and environmental enrichment, respectively, on the functional maturation of these cells. Altogether, our data shed light on novel functions of Tau protein related to the plastic modulation of adult hippocampal neurogenesis by external stimuli.
Tau plays a novel in vivo role in the synaptic maturation of newborn granule neurons under basal conditions.
Tau is involved in immature granule neuron cell death caused by acute stress.
Tau regulates the stress‐induced impairment of newborn granule neuron functional maturation.
Tau regulates the increase in newborn neuron survival triggered by environmental enrichment.
Tau modulates the stimulatory effects of environmental enrichment on the functional maturation of newborn granule neurons.
The EMBO Journal (2016) 35: 1417–1436
- Received November 18, 2015.
- Revision received April 1, 2016.
- Accepted April 21, 2016.
- © 2016 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.
- NB‐3 signaling mediates the cross‐talk between post‐traumatic spinal axons and scar‐forming cells
- Zhenhui Huang1,†,
- Yarong Gao1,†,
- Yuhui Sun1,†,
- Chao Zhang2,
- Yue Yin1,
- Yasushi Shimoda3,
- Kazutada Watanabe4 and
- Yaobo Liu (liuyaobo{at}suda.edu.cn)*,1
- 1Institute of Neuroscience, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro‐Psycho‐Diseases, Soochow University, Suzhou, China
- 2The Medical School of Lanzhou University, Lanzhou, China
- 3Department of Bioengineering, Nagaoka University of Technology, Niigata, Japan
- 4National Institute of Technology, Nagaoka College, Niigata, Japan
- ↵*Corresponding author. Tel: +86 512 65882526; E‐mail: liuyaobo{at}suda.edu.cn
↵† These authors contributed equally to this work
The neural recognition molecule NB‐3 negatively regulates axon regeneration by promoting trans‐homophilic interactions between injured axons and scar‐forming cells to suppress axon growth.
Synopsis
NB‐3 trans‐homophilic interactions mediate the molecular cross‐talk between post‐traumatic axons and scar‐forming cells and impair the intrinsic growth ability of injured axons by modulating mTOR activity via CHL1 and PTPσ.
SCI‐induced NB‐3 in injured axons and scar‐forming cells interacts homophilically.
Interruption of NB‐3 homophilic binding enhances regrowth of corticospinal axons.
Trans‐homophilic interactions of NB‐3 downregulate mTOR signaling via CHL1 and PTPσ.
The EMBO Journal (2016) 35: 1745–1765
- Received November 11, 2015.
- Revision received March 20, 2016.
- Accepted April 12, 2016.
- © 2016 The Authors
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