title: Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour.
abstract: Myotonic dystrophy type 1 is a complex multisystemic inherited disorder, which displays multiple debilitating neurological manifestations. Despite recent progress in the understanding of the molecular pathogenesis of myotonic dystrophy type 1 in skeletal muscle and heart, the pathways affected in the central nervous system are largely unknown. To address this question, we studied the only transgenic mouse line expressing CTG trinucleotide repeats in the central nervous system. These mice recreate molecular features of RNA toxicity, such as RNA foci accumulation and missplicing. They exhibit relevant behavioural and cognitive phenotypes, deficits in short-term synaptic plasticity, as well as changes in neurochemical levels. In the search for disease intermediates affected by disease mutation, a global proteomics approach revealed RAB3A upregulation and synapsin I hyperphosphorylation in the central nervous system of transgenic mice, transfected cells and post-mortem brains of patients with myotonic dystrophy type 1. These protein defects were associated with electrophysiological and behavioural deficits in mice and altered spontaneous neurosecretion in cell culture. Taking advantage of a relevant transgenic mouse of a complex human disease, we found a novel connection between physiological phenotypes and synaptic protein dysregulation, indicative of synaptic dysfunction in myotonic dystrophy type 1 brain pathology.
authors: Inserm U781, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants Malades, 75015 Paris, France. mario.pereira@inserm.fr
authors: Oscar
authors: O
authors: Hernández-Hernández
authors: Céline
authors: C
authors: Guiraud-Dogan
authors: Géraldine
authors: G
authors: Sicot
authors: Aline
authors: A
authors: Huguet
authors: Sabrina
authors: S
authors: Luilier
authors: Esther
authors: E
authors: Steidl
authors: Stefanie
authors: S
authors: Saenger
authors: Elodie
authors: E
authors: Marciniak
authors: Hélène
authors: H
authors: Obriot
authors: Caroline
authors: C
authors: Chevarin
authors: Annie
authors: A
authors: Nicole
authors: Lucile
authors: L
authors: Revillod
authors: Konstantinos
authors: K
authors: Charizanis
authors: Kuang-Yung
authors: KY
authors: Lee
authors: Yasuhiro
authors: Y
authors: Suzuki
authors: Takashi
authors: T
authors: Kimura
authors: Tohru
authors: T
authors: Matsuura
authors: Bulmaro
authors: B
authors: Cisneros
authors: Maurice S
authors: MS
authors: Swanson
authors: Fabrice
authors: F
authors: Trovero
authors: Bruno
authors: B
authors: Buisson
authors: Jean-Charles
authors: JC
authors: Bizot
authors: Michel
authors: M
authors: Hamon
authors: Sandrine
authors: S
authors: Humez
authors: Guillaume
authors: G
authors: Bassez
authors: Friedrich
authors: F
authors: Metzger
authors: Luc
authors: L
authors: Buée
authors: Arnold
authors: A
authors: Munnich
authors: Nicolas
authors: N
authors: Sergeant
authors: Geneviève
authors: G
authors: Gourdon
authors: Mário
authors: M
authors: Gomes-Pereira
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D015153:Blotting, Western; D015180:Electrophoresis, Gel, Two-Dimensional; D004594:Electrophysiology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009223:Myotonic Dystrophy / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion
references: J Biol Chem. 2001 Mar 16;276(11):7820-6
references: 11124939
references: Hum Mol Genet. 2009 Apr 15;18(8):1471-81
references: 19223393
references: J Neuropathol Exp Neurol. 2008 Apr;67(4):319-25
references: 18379436
references: J Biol Chem. 2009 Jan 2;284(1):174-181
references: 19004831
references: J Neurochem. 2003 Jun;85(6):1581-91
references: 12787077
references: Science. 1992 Mar 6;255(5049):1253-5
references: 1546325
references: J Cell Sci. 2007 Sep 15;120(Pt 18):3228-37
references: 17726061
references: Neurology. 2006 Jul 25;67(2):350-2
references: 16864839
references: Nature. 1997 Jun 19;387(6635):810-4
references: 9194562
references: Acta Neurobiol Exp (Wars). 2007;67(4):481-8
references: 18320725
references: Nat Genet. 2001 Sep;29(1):40-7
references: 11528389
references: Neuromuscul Disord. 2005 Apr;15(4):287-92
references: 15792867
references: PLoS One. 2009;4(1):e4326
references: 19177164
references: Mutat Res. 2006 Jun 25;598(1-2):15-34
references: 16500684
references: Neuroscience. 2010 Sep 15;169(4):1589-600
references: 20600668
references: Annu Rev Neurosci. 2009;32:267-87
references: 19555290
references: Arch Neurol. 2004 Dec;61(12):1943-7
references: 15596617
references: PLoS One. 2012;7(3):e33218
references: 22427994
references: Cell. 1993 Nov 19;75(4):661-70
references: 7902212
references: Biochim Biophys Acta. 2007 Dec;1772(11-12):1183-91
references: 17950578
references: Brain. 2011 Dec;134(Pt 12):3530-46
references: 22131273
references: Neurology. 2010 Apr 6;74(14):1108-17
references: 20220122
references: Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2646-51
references: 18272483
references: Mol Cell. 2002 Jul;10(1):35-44
references: 12150905
references: Am J Electroneurodiagnostic Technol. 2006 Mar;46(1):18-38
references: 16605170
references: Mol Cell. 2007 Oct 12;28(1):68-78
references: 17936705
references: J Neuropathol Exp Neurol. 2008 Aug;67(8):763-72
references: 18648326
references: Neurology. 1999 Sep 22;53(5):1042-50
references: 10496264
references: J Neurosci. 2011 Mar 9;31(10):3580-8
references: 21389214
references: J Neurol Neurosurg Psychiatry. 1998 Sep;65(3):353-6
references: 9728948
references: Cereb Cortex. 2009 Jun;19(6):1422-39
references: 19020204
references: J Clin Invest. 2007 Oct;117(10):2802-11
references: 17823658
references: PLoS Genet. 2012;8(11):e1003043
references: 23209425
references: Psychol Med. 2010 Mar;40(3):487-95
references: 19627641
references: Cell. 1992 Feb 21;68(4):799-808
references: 1310900
references: Neurology. 1998 Feb;50(2):535-8
references: 9484393
references: Neurol Sci. 2010 Dec;31(6):757-63
references: 20842397
references: Neuromuscul Disord. 2007 Jun;17(6):451-8
references: 17433680
references: Annu Rev Neurosci. 2006;29:259-77
references: 16776586
references: Nat Struct Mol Biol. 2011 Jun 19;18(7):840-5
references: 21685920
references: J Biol Chem. 2002 Oct 25;277(43):40919-29
references: 12167638
references: PLoS Genet. 2007 Apr 6;3(4):e52
references: 17411343
references: Science. 2003 Dec 12;302(5652):1978-80
references: 14671308
references: Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20333-8
references: 19075228
references: Neuromuscul Disord. 2011 Feb;21(2):81-8
references: 21169019
references: Neuromuscul Disord. 2003 Dec;13(10):813-21
references: 14678804
references: EMBO J. 2000 Sep 1;19(17):4439-48
references: 10970838
references: Hum Mol Genet. 2006 Jul 1;15(13):2087-97
references: 16717059
references: Muscle Nerve. 2007 Sep;36(3):294-306
references: 17486579
references: Annu Rev Neurosci. 2004;27:509-47
references: 15217342
references: J Transl Med. 2010 May 20;8:48
references: 20487562
references: Hum Mol Genet. 2000 May 1;9(8):1185-94
references: 10767343
references: Mol Cell. 2002 Jul;10(1):45-53
references: 12150906
references: Neurology. 1992 Jan;42(1):91-4
references: 1734329
references: Neurology. 1998 Oct;51(4):1121-4
references: 9781540
references: Science. 1992 Mar 6;255(5049):1256-8
references: 1546326
references: Brain Cell Biol. 2006 Jun;35(2-3):107-15
references: 17957477
references: Methods. 2004 Aug;33(4):267-72
references: 15183174
references: Eur J Neurosci. 2004 Apr;19(7):1895-905
references: 15078563
references: Hum Mol Genet. 2001 Nov 1;10(23):2717-26
references: 11726559
references: Arch Neurol. 1998 May;55(5):635-40
references: 9605719
references: Int J Neurosci. 2010 Jul;120(7):455-70
references: 20583898
references: Brain Res. 2006 Jun 22;1096(1):70-84
references: 16716268
references: Am J Physiol Cell Physiol. 2007 Apr;292(4):C1291-7
references: 17135300
references: Neuron. 2012 Aug 9;75(3):437-50
references: 22884328
references: Sci Rep. 2012;2:209
references: 22355723
references: Hum Mol Genet. 2004 Dec 15;13(24):3079-88
references: 15496431
references: Nat Med. 2012 Jul;18(7):1136-41
references: 22660636
references: Neurosci Lett. 2007 Jun 27;421(2):178-83
references: 17566645