- Research ArticleHigh‐affinity interactions and signal transduction between Aβ oligomers and TREM2
- Christian B Lessard1,
- Samuel L Malnik1,
- Yingyue Zhou2,
- Thomas B Ladd1,
- Pedro E Cruz1,
- Yong Ran1,
- Thomas E Mahan3,
- Paramita Chakrabaty1,4,
- David M Holtzman3,
- Jason D Ulrich3,
- Marco Colonna2 and
- Todd E Golde (tgolde{at}ufl.edu)*,1,4
- 1Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, FL, USA
- 2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
- 3Department of Neurology, Hope Center for Neurological Disorders, Knight ADRC, Washington University School of Medicine, St. Louis, MO, USA
- 4McKnight Brain Institute, University of Florida, Gainesville, FL, USA
- ↵*Corresponding author. Tel: +1 352 273 9458; Fax +1 352 294 5060; E‐mail: tgolde{at}ufl.edu
Rare coding variants of TREM2 (R47H, R62H) are associated with increased risk for Alzheimer's disease (AD), but how they confer this risk remains uncertain. Using BioLayer Interferometry and other biochemical methods, TREM2 and AD‐associated variants binding to Aβ and APOE is examined.
Synopsis
Rare coding variants of TREM2 (R47H, R62H) are associated with increased risk for Alzheimer's disease (AD), but how they confer this risk remains uncertain. Using BioLayer Interferometry and other biochemical methods, TREM2 and AD‐associated variants binding to Aβ and APOE is examined.
High‐affinity binding of TREM2 to Aβ oligomers is characterized by very slow dissociation which is almost “irreversible”.
Pre‐incubation of TREM2 with Aβ oligomers is shown to block its interaction with APOE.
AD‐associated TREM2 variants bound Aβ with equivalent affinity.
AD‐associated TREM2 variants reduced Aβ42 internalization and NFAT signaling activity.
AD‐associated TREM2 variants showed a partial loss of function.
EMBO Mol Med (2018) e9027
- Received February 21, 2018.
- Revision received September 13, 2018.
- Accepted September 17, 2018.
- © 2018 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.
- News & ViewsCancer immunotherapy in routine cost‐effective cancer care?
- Sir Marc Feldmann (marc.feldmann{at}kennedy.ox.ac.uk)1
Therapy‐triggered autoimmunity and inflammation in many cancer patients, as well as treatment costs, hamper the success of cancer immunotherapy. The study by Pfeiffer et al in this issue of EMBO Molecular Medicine constitutes a clear step towards a more simple, scalable and affordable approach in generating in situ T cells reprogrammed with chimeric antigen receptors (CARs) (Pfeiffer et al, 2018).
See also: Pfeiffer et al
M. Feldmann discusses the in vivo generation of T cells reprogrammed with chimeric antigen receptors reported in this issue of EMBO Molecular Medicine by Pfeiffer et al.
EMBO Mol Med (2018) e9660
- © 2018 The Author. 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.
- News & ViewsA promising, novel, and unique BACE1 inhibitor emerges in the quest to prevent Alzheimer's disease
A major hallmark of Alzheimer's disease (AD) is the deposition of amyloid‐beta (Aβ) plaques in the brain. Sequential cleavage of amyloid precursor protein by BACE1 and γ‐secretase generates Aβ. Thus, BACE1 is an attractive AD drug target. Although many BACE1 inhibitors have advanced to clinical trials, most have failed. Some failures may be due to treatment occurring at a late stage when Aβ levels have already led to irreversible neurodegeneration; therefore, there has been a shift toward therapeutic intervention during presymptomatic AD. In this issue of EMBO Molecular Medicine, Neumann et al comprehensively introduce the novel BACE1 inhibitor, CNP520. Their rigorous and robust results stem from in vitro studies, animal models, as well as initial human clinical studies that indicate CNP520 is an exquisitely safe therapeutic agent making it particularly attractive for the prevention of AD. As CNP520 is currently in a clinical trial of presymptomatic individuals at risk for AD, it will be among the first of BACE1 inhibitors to test the prevention paradigm for AD.
See also: U Neumann et al
RJ Vassar and JA Dobrowolska Zakaria discuss the study of Neumann et al who comprehensively introduce the novel BACE1 inhibitor, CNP520, as a safe therapeutic agent making it particularly attractive for the prevention of Alzheimer's disease.
EMBO Mol Med (2018) e9717
- © 2018 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.
- Research ArticleRapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis
- Gabriele Civiletto1,
- Sukru Anil Dogan1,
- Raffaele Cerutti1,
- Gigliola Fagiolari2,
- Maurizio Moggio2,
- Costanza Lamperti3,
- Cristiane Benincá1,
- Carlo Viscomi (cfv23{at}mrc-mbu.cam.ac.uk)*,1 and
- Massimo Zeviani (mdz21{at}mrc-mbu.cam.ac.uk)*,1
- 1MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
- 2Neuromuscular and Rare Diseases Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- 3IRCCS Foundation Neurological Institute “C. Besta”, Milano, Italy
- ↵*
Corresponding author. Tel: +44 1223 252804; Fax: +44 1223 252715; E‐mail: cfv23{at}mrc-mbu.cam.ac.uk
Corresponding author. Tel: +44 1223 252700; Fax: +44 1223 252715; E‐mail: mdz21{at}mrc-mbu.cam.ac.uk
Mitochondrial diseases are a large family of genetic disorders for which no cure is currently available. Rapamycin, a TORC1‐dependent autophagy activator, ameliorates the phenotype a muscle‐specific Cox15sm/sm mouse model of severe mitochondrial myopathy.
Synopsis
Mitochondrial diseases are a large family of genetic disorders for which no cure is currently available. Rapamycin, a TORC1‐dependent autophagy activator, ameliorates the phenotype a muscle‐specific Cox15sm/sm mouse model of severe mitochondrial myopathy.
Rapamycin increases the reduced autophagic flux in the skeletal muscle of Cox15sm/sm mice.
Rilmenidine, a mTORC1‐independent autophagy inducer, increases autophagy without rescuing the phenotype of Cox15sm/sm mice.
By inhibiting mTORC1, rapamycin induces the translocation of TFEB to the nucleus, inducing lysosomal biogenesis.
The coordinated activation of autophagy and lysosomal biogenesis contributes to the beneficial effects of rapamycin in Cox15sm/sm mice.
EMBO Mol Med (2018) e8799
- Received December 19, 2017.
- Revision received September 12, 2018.
- Accepted September 17, 2018.
- © 2018 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.
- Research ArticleReinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator
- Snehajyoti Chatterjee1,2,†,
- Raphaelle Cassel1,2,†,
- Anne Schneider‐Anthony1,2,†,
- Karine Merienne1,2,
- Brigitte Cosquer1,2,
- Laura Tzeplaeff1,2,
- Sarmistha Halder Sinha3,
- Manoj Kumar3,
- Piyush Chaturbedy4,
- Muthusamy Eswaramoorthy4,
- Stéphanie Le Gras5,
- Céline Keime5,
- Olivier Bousiges1,6,
- Patrick Dutar7,
- Petnoi Petsophonsakul8,
- Claire Rampon8,
- Jean‐Christophe Cassel1,2,
- Luc Buée9,
- David Blum9,
- Tapas K Kundu (tapas{at}jncasr.ac.in)*,3 and
- Anne‐Laurence Boutillier (laurette{at}unistra.fr)*,1,2
- 1Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Université de Strasbourg, Strasbourg, France
- 2LNCA, CNRS UMR 7364, Strasbourg, France
- 3Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
- 4Chemistry and Physics of Materials Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
- 5CNRS, Inserm, UMR 7104, Microarray and Sequencing Platform, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France
- 6Laboratory of Biochemistry and Molecular Biology, Hôpital de Hautepierre, University Hospital of Strasbourg, Strasbourg, France
- 7Centre de Psychiatrie et Neurosciences, INSERM UMRS894, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
- 8Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, CNRS, UPS, Université de Toulouse, Toulouse, France
- 9Inserm, CHU‐Lille, UMR‐S 1172, Alzheimer & Tauopathies, Université de Lille, Lille, France
- ↵*
Corresponding author. Tel: +91 80 2208 2840; E‐mail: tapas{at}jncasr.ac.in
Corresponding author. Tel: +33 3688 51934; E‐mail: laurette{at}unistra.fr
↵† These authors contributed equally to this work
Epigenetic dysfunctions related to H2B histone acetylation were shown in the hippocampus of a mouse model of Alzheimer's disease. A therapeutic strategy aimed at activating CBP/p300 acetyltransferase revealed efficient at rescuing neuronal activity, plasticity and memory in these mice.
Synopsis
Epigenetic dysfunctions related to H2B histone acetylation were shown in the hippocampus of a mouse model of Alzheimer's disease. A therapeutic strategy aimed at activating CBP/p300 acetyltransferase revealed efficient at rescuing neuronal activity, plasticity and memory in these mice.
Alzheimer‐related tau pathology is associated with epigenetic dysfunctions.
A balanced H2Bac epigenomic landscape is maintained by CBP/HAT activity and important for hippocampus‐dependent learning and memory.
A new therapeutic strategy to restore memory in cognitive diseases can be achieved by pharmacological activation of CBP/p300 acetyltransferases with CSP‐TTK21.
EMBO Mol Med (2018) e8587
- Received October 16, 2017.
- Revision received August 31, 2018.
- Accepted September 5, 2018.
- © 2018 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.
- Research ArticleEarly auto‐immune targeting of photoreceptor ribbon synapses in mouse models of multiple sclerosis
- Mayur Dembla (dotdot.mayur{at}gmail.com)*,1,
- Ajay Kesharwani1,
- Sivaraman Natarajan1,4,
- Claudia Fecher‐Trost2,
- Richard Fairless3,
- Sarah K Williams3,
- Veit Flockerzi2,
- Ricarda Diem3,
- Karin Schwarz (Karin.Schwarz{at}uks.eu)*,1 and
- Frank Schmitz (frank.schmitz{at}uks.eu)*,1
- 1Department of Neuroanatomy, Institute of Anatomy and Cell Biology, Medical School, Saarland University, Homburg, Germany
- 2Institute of Experimental and Clinical Pharmacology and Toxicology, Medical School, Saarland University, Homburg, Germany
- 3Department of Neurology, University Clinic Heidelberg, Heidelberg, Germany
- 4Present Address: St. Jude Children's Research Hospital, Memphis, TN, USA
- ↵*
Corresponding author. Tel: +49 6841 1626195; E‐mail: dotdot.mayur{at}gmail.com
Corresponding author. Tel: +49 6841 1626199; E‐mail: Karin.Schwarz{at}uks.eu
Corresponding author. Tel: +49 6841 1626012; E‐mail: frank.schmitz{at}uks.eu
The primary events that lead to optic neuritis (ON) in multiple sclerosis (MS) remain unclear. The paranodal protein CASPR1 is expressed at retinal ribbon synapses and is strongly affected in animal models of MS/ON. Synaptic alterations within the retina precede demyelination in the optic nerve.
Synopsis
The primary events that lead to optic neuritis (ON) in multiple sclerosis (MS) remain unclear. The paranodal protein CASPR1 is expressed at retinal ribbon synapses and is strongly affected in animal models of MS/ON. Synaptic alterations within the retina precede demyelination in the optic nerve.
The paranodal adhesion proteins CASPR1 and CNTN1 are highly enriched at retinal ribbon synapses.
Expression of both CASPR1 and CNTN1 is decreased in mouse models of ON before the onset of clinical symptoms.
Retinal ribbon synapses are targeted by an auto‐reactive immune system in the pre‐clinical phase of experimental autoimmune encephalomyelitis before morphologically visible changes in the optic nerve occur.
Altered synaptic vesicle cycling and altered visual behavior precede demyelination of the optic nerve.
EMBO Mol Med (2018) e8926
- Received January 28, 2018.
- Revision received August 31, 2018.
- Accepted September 4, 2018.
- © 2018 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.
- Research ArticleUSP14 inhibition corrects an in vivo model of impaired mitophagy
- Joy Chakraborty1,
- Sophia von Stockum2,
- Elena Marchesan2,
- Federico Caicci1,
- Vanni Ferrari1,
- Aleksandar Rakovic3,
- Christine Klein3,
- Angelo Antonini4,
- Luigi Bubacco1 and
- Elena Ziviani (elena.ziviani{at}unipd.it)*,1,2
- 1Department of Biology, University of Padova, Padova, Italy
- 2Fondazione Ospedale San Camillo IRCCS, Venezia, Italia
- 3Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
- 4Department of Neuroscience, University of Padova, Padova, Italy
- ↵*Corresponding author. Tel: +39 49 827 6237: E‐mail elena.ziviani{at}unipd.it
Mitophagy depends on proteasome complex and autophagy; both are known to be influenced by USP14. USP14 interference is shown to enhance both processes and boost mitophagy. In vivo, USP14 can be targeted where mitophagy is hindered, as shown in a Parkinson's disease fly model.
Synopsis
Mitophagy depends on proteasome complex and autophagy; both are known to be influenced by USP14. USP14 interference is shown to enhance both processes and boost mitophagy. In vivo, USP14 can be targeted where mitophagy is hindered, as shown in a Parkinson's disease fly model.
USP14 inhibition enhances mitochondrial clearance in neuronal cell line and in PINK1/Parkin deficient cells.
Mitochondrial membrane rupture is enhanced by USP14 inhibition, which leads to PHB2‐LC3 interaction mediated mitophagy.
USP14 knock down ameliorates Parkinsonian symptoms in a PINK1/Parkin mutation‐induced Drosophila model of Parkinson's disease.
EMBO Mol Med (2018) e9014
- Received February 19, 2018.
- Revision received August 22, 2018.
- Accepted August 24, 2018.
- © 2018 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.
