Neuroscience
- One more factor joins the plot: Pbx1 regulates differentiation and survival of midbrain dopaminergic neurons
- Diogo S Castro (dscastro{at}igc.gulbenkian.pt)1
Midbrain dopaminergic neurons have been the subject of intense research, because of their importance in pathologies such as Parkinson's disease. In this issue of The EMBO Journal, Villaescusa et al (2016) show the transcription factor Pbx1 is required for the differentiation and survival of midbrain dopaminergic neurons. Notably, Pbx1 protects from oxidative stress by inducing Nfe2l1, and the expression of both genes is reduced in dopaminergic neurons from Parkinson's patients. This is an important study, with possible implications in regenerative medicine and drug design.
See also: JC Villaescusa et al (September 2016)
The homeobox transcription factor Pbx1 regulates dopaminergic neuronal development and protects them from oxidative stress.
- © 2016 The Author
- Loss of FBXO7 (PARK15) results in reduced proteasome activity and models a parkinsonism‐like phenotype in mice
- Siv Vingill1,2,†,
- David Brockelt1,2,†,
- Camille Lancelin3,‡,
- Lars Tatenhorst4,5,‡,
- Guergana Dontcheva1,2,6,
- Christian Preisinger7,
- Nicola Schwedhelm‐Domeyer1,
- Sabitha Joseph1,2,6,
- Miso Mitkovski8,
- Sandra Goebbels9,
- Klaus‐Armin Nave5,9,
- Jörg B Schulz6,
- Till Marquardt3,5,10,
- Paul Lingor4,5 and
- Judith Stegmüller (jstegmueller{at}ukaachen.de)*,1,5,6
- 1Cellular and Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany
- 2Neuroscience, International Max Planck Research School, Göttingen, Germany
- 3European Neuroscience Institute (ENI), Göttingen, Germany
- 4Neurology, University Medical Center, Göttingen, Germany
- 5Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CMPB), Göttingen, Germany
- 6Department of Neurology, University Hospital, RWTH Aachen, Aachen, Germany
- 7Proteomics Facility, Interdisciplinary Center for Clinical Research (IZKF) Aachen, Medical Faculty, RWTH Aachen, Aachen, Germany
- 8Light Microscopy Facility, Max Planck Institute of Experimental Medicine, Göttingen, Germany
- 9Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany
- 10Section Neurobiological Research, Department of Neurology, University Hospital, RWTH Aachen, Aachen, Germany
- ↵*Corresponding author. Tel: +49 241 8085 793; E‐mail: jstegmueller{at}ukaachen.de
Mouse knockout of FBXO7, associated with early‐onset Parkinson's disease, affects the assembly state of proteasomes and causes motor impairments strikingly resembling those seen in patients.
Synopsis
Systemic and conditional loss of the parkinsonian pyramidal syndrome‐associated protein FBXO7 (PARK15) in mice triggers motor impairment. At the neuronal level, the E3 ligase FBXO7‐SCF associates with proteasomes and regulates their assembly.
FBXO7‐SCF binds to and ubiquitinates the proteasomal subunit PSMA2.
FBXO7 affects the assembly state and activity of the proteasome in the cells including neurons.
Systemic deletion of FBXO7 leads to premature death and motor disabilities.
Deletion of FBXO7 from forebrain and dopaminergic neurons triggers early‐ and late‐onset motor impairment, respectively.
The EMBO Journal (2016) 35: 2008–2025
- Received November 30, 2015.
- Revision received June 13, 2016.
- Accepted July 7, 2016.
- © 2016 The Authors
- Synaptonuclear messenger PRR7 inhibits c‐Jun ubiquitination and regulates NMDA‐mediated excitotoxicity
- Dana O Kravchick1,
- Anna Karpova2,
- Matous Hrdinka2,
- Jeffrey Lopez‐Rojas2,
- Sanda Iacobas3,
- Abigail U Carbonell1,
- Dumitru A Iacobas3,
- Michael R Kreutz2,4 and
- Bryen A Jordan*,1,5
- 1Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA
- 2Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany
- 3Department of Pathology, New York Medical College, Valhalla, NY, USA
- 4Leibniz Group “Dendritic Organelles and Synaptic Function”, Center for Molecular Neurobiology, University Medical Center Hamburg‐Eppendorf, Hamburg, Germany
- 5Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA
- ↵*Corresponding author. Tel: +1 718 430 2675; E‐mail: bryen.jordan{at}einstein.yu.edu
The synaptic protein PRR7 is a mediator of NMDA receptor‐induced c‐Jun stabilization that leads to neuronal apoptosis in conditions such as neurodegenerative disease, stroke, or epilepsy.
Synopsis
The transcription factor c‐Jun regulates NMDA receptor‐dependent neuronal death. Proline rich 7 (PRR7) is a synaptic protein that shuttles to the nucleus upon NMDA receptor stimulation, upregulates c‐Jun abundance by inhibiting its ubiquitination, and plays a role in neuronal excitotoxicity.
PRR7 binds to NMDA receptors and is a novel activity‐dependent synaptonuclear messenger in hippocampal neurons.
PRR7 inhibits the ubiquitination of c‐Jun by the SCF‐complex E3 ligase, FBW7.
PRR7 nuclear transport elevates c‐Jun abundance, increases c‐Jun transcriptional activity, and promotes neuronal death.
PRR7 activity regulates transcripts associated with cellular viability, and loss of PRR7 is neuroprotective.
The EMBO Journal (2016) 35: 1923–1934
- Received September 14, 2015.
- Revision received June 17, 2016.
- Accepted June 21, 2016.
- © 2016 The Authors
- Tryptophan‐rich basic protein (WRB) mediates insertion of the tail‐anchored protein otoferlin and is required for hair cell exocytosis and hearing
- Christian Vogl1,2,†,
- Iliana Panou1,2,3,†,
- Gulnara Yamanbaeva2,4,†,
- Carolin Wichmann2,5,†,
- Sara J Mangosing6,†,
- Fabio Vilardi7,†,
- Artur A Indzhykulian8,†,
- Tina Pangršič2,9,†,
- Rosamaria Santarelli10,11,
- Montserrat Rodriguez‐Ballesteros12,
- Thomas Weber1,
- Sangyong Jung1,13,
- Elena Cardenas6,
- Xudong Wu8,
- Sonja M Wojcik14,
- Kelvin Y Kwan15,
- Ignacio del Castillo12,16,
- Blanche Schwappach7,
- Nicola Strenzke2,4,
- David P Corey (david_corey{at}hms.harvard.edu)*,8,
- Shuh‐Yow Lin (shuh-yow{at}ucsd.edu)*,6 and
- Tobias Moser (tmoser{at}gwdg.de)*,1,2,13,17
- 1Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany
- 2Collaborative Research Center 889, University of Göttingen, Göttingen, Germany
- 3Göttingen Graduate School for Neurosciences, Biophysics and Molecular Biosciences, University of Göttingen, Göttingen, Germany
- 4Auditory Systems Physiology Group and InnerEarLab, Department of Otolaryngology, University of Göttingen Medical Center, Göttingen, Germany
- 5Molecular Architecture of Synapses Group, Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany
- 6Otolaryngology Division, Department of Surgery, School of Medicine, University of California San Diego, La Jolla, CA, USA
- 7Institute of Molecular Biology, University Medical Center Göttingen, Göttingen, Germany
- 8Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, MA, USA
- 9Synaptic Physiology of Mammalian Vestibular Hair Cells Junior Research Group, Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany
- 10Department of Neurosciences, University of Padova, Padova, Italy
- 11Audiology and Phoniatrics Service, Treviso Regional Hospital, Treviso, Italy
- 12Servicio de Genetica, Hospital Universitario Ramon y Cajal, IRYCIS, Madrid, Spain
- 13Synaptic Nanophysiology Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
- 14Department of Molecular Neurobiology, Max‐Planck‐Institute for Experimental Medicine, Göttingen, Germany
- 15W. M. Keck Center for Collaborative Neuroscience, Nelson Lab‐D250, Rutgers University, Piscataway, NJ, USA
- 16Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
- 17Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany
- ↵*
Corresponding author. Tel: +1 617 432 2506; E‐mail: david_corey{at}hms.harvard.edu
Corresponding author. Tel: +1 858 822 3297; E‐mail: shuh-yow{at}ucsd.edu
Corresponding author. Tel: +49 551 3922803; E‐mail: tmoser{at}gwdg.de
↵† These authors contributed equally to this work
ER membrane insertion of the sensory hair cell component otoferlin depends on the tail‐anchored protein insertion TRC40 pathway, whose disruption impairs synaptic vesicle replenishment and hearing.
Synopsis
Otoferlin, a tail‐anchored protein of sensory hair cells, uses the transmembrane recognition complex (TRC40) pathway for ER membrane insertion. Disruption of the TRC40 receptor Wrb in hair cells impaired vesicle replenishment and hearing, most likely by reducing otoferlin levels.
Hearing requires membrane insertion of tail‐anchored (TA) proteins by the TRC40 pathway in hair cells.
The TA protein otoferlin, essential for hair cell exocytosis and defective in human deafness, utilizes the TRC40 pathway.
Deletion of TRC40 receptor WRB reduces otoferlin levels and impairs synaptic structure and function.
Reduced vesicle replenishment in WRB‐deficient hair cells impairs sound encoding.
The EMBO Journal (2016) 35: 2536–2552
- Received November 30, 2015.
- Revision received May 29, 2016.
- Accepted June 10, 2016.
- © 2016 The Authors
- Dopamine helps worms deal with stress
To maintain protein homoeostasis, animals have developed stress response pathways such as the ubiquitin proteasome system (UPS). Joshi and colleagues have demonstrated that in Caenorhabditis elegans, dopamine release from neurons acts on receptors in the epithelia to modulate protein turnover, by controlling the expression of regulators of the xenobiotic stress response. Dopamine receptor mutants challenged with pathogenic bacteria were defective in protein turnover and were also more sensitive to infection thus highlighting a role for monoamine signalling in innate immunity and stress responses.
See also: KK Joshi et al (September 2016)
Neuronal dopamine release modulates epithelial protein homoeostasis to regulate innate immunity and stress responses.
- © 2016 The Authors
- 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
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