title: The wobbler mouse, an ALS animal model.
abstract: This review article is focused on the research progress made utilizing the wobbler mouse as animal model for human motor neuron diseases, especially the amyotrophic lateral sclerosis (ALS). The wobbler mouse develops progressive degeneration of upper and lower motor neurons and shows striking similarities to ALS. The cellular effects of the wobbler mutation, cellular transport defects, neurofilament aggregation, neuronal hyperexcitability and neuroinflammation closely resemble human ALS. Now, 57 years after the first report on the wobbler mouse we summarize the progress made in understanding the disease mechanism and testing various therapeutic approaches and discuss the relevance of these advances for human ALS. The identification of the causative mutation linking the wobbler mutation to a vesicle transport factor and the research focussed on the cellular basis and the therapeutic treatment of the wobbler motor neuron degeneration has shed new light on the molecular pathology of the disease and might contribute to the understanding the complexity of ALS.
authors.affiliation: Molecular Biology and Genetics Department, Aarhus University, C. F. Møllers Alle 3, 8000 Aarhus C, Denmark.
authors.forename: Jakob Maximilian
authors.initials: JM
authors.lastname: Moser
authors.forename: Paolo
authors.initials: P
authors.lastname: Bigini
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmitt-John
mesh_terms: D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D016472:Motor Neuron Disease / Q000209:etiology*; D009154:Mutation; D013091:Spermatogenesis / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; C486749:VPS54 protein, human; D033921:Vesicular Transport Proteins; C486750:Vps54 protein, mouse
references.citation: Nat Genet. 2006 Apr;38(4):411-3
references.pmid: 16501576
references.citation: Neuropharmacology. 1985 Nov;24(11):1085-92
references.pmid: 3001571
references.citation: N Engl J Med. 1992 May 28;326(22):1464-8
references.pmid: 1349424
references.citation: Mol Cell Biol. 2009 Oct;29(19):5251-63
references.pmid: 19620288
references.citation: Neurobiol Dis. 2005 Feb;18(1):126-33
references.pmid: 15649703
references.citation: PLoS One. 2010 Mar 24;5(3):e9872
references.pmid: 20352044
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18809-14
references.pmid: 19833869
references.citation: Neuron. 2011 Oct 20;72(2):257-68
references.pmid: 21944779
references.citation: Mol Med. 2012 Sep 07;18:971-81
references.pmid: 22562723
references.citation: Nature. 2011 Aug 21;477(7363):211-5
references.pmid: 21857683
references.citation: Differentiation. 1991 Jul;47(2):77-83
references.pmid: 1955109
references.citation: Nat Genet. 1996 Nov;14(3):269-76
references.pmid: 8896555
references.citation: PLoS One. 2008 Aug 06;3(8):e2849
references.pmid: 18682740
references.citation: Brain Res. 2008 Feb 21;1195:56-66
references.pmid: 18206859
references.citation: Cell Death Differ. 2004 Jul;11 Suppl 1:S37-44
references.pmid: 15243580
references.citation: BMC Genet. 2002 Aug 13;3:14
references.pmid: 12174196
references.citation: Trends Cell Biol. 2011 Mar;21(3):159-67
references.pmid: 21183348
references.citation: Brain Res. 1994 Jul 11;650(2):353-7
references.pmid: 7953705
references.citation: J Neurosci Res. 1998 Mar 1;51(5):559-62
references.pmid: 9511999
references.citation: Neurobiol Dis. 2011 Mar;41(3):695-705
references.pmid: 21168498
references.citation: Mol Med. 2006 Jul-Aug;12(7-8):153-60
references.pmid: 17088947
references.citation: Neuroscience. 2010 Sep 15;169(4):1621-9
references.pmid: 20600671
references.citation: Mol Neurodegener. 2009 Jul 20;4:31
references.pmid: 19619317
references.citation: Eur J Neurosci. 2002 Dec;16(12):2291-6
references.pmid: 12492423
references.citation: Exp Neurol. 2003 Aug;182(2):412-20
references.pmid: 12895451
references.citation: Am J Hum Genet. 2004 Nov;75(5):822-31
references.pmid: 15372378
references.citation: J Cell Sci. 2002 Jul 1;115(Pt 13):2627-37
references.pmid: 12077354
references.citation: Amyotroph Lateral Scler. 2011 Jan;12(1):1-10
references.pmid: 20698807
references.citation: Mol Neurobiol. 2009 Apr;39(2):81-9
references.pmid: 19184563
references.citation: Mol Biol Cell. 2008 Jun;19(6):2350-62
references.pmid: 18367545
references.citation: Neuromuscul Disord. 1995 Sep;5(5):383-90
references.pmid: 7496172
references.citation: Amyotroph Lateral Scler. 2008 Jun;9(3):141-8
references.pmid: 18574757
references.citation: FEBS Lett. 2004 Mar 12;561(1-3):191-4
references.pmid: 15013776
references.citation: Dis Model Mech. 2010 Sep-Oct;3(9-10):652-62
references.pmid: 20504969
references.citation: PLoS One. 2008 Jun 25;3(6):e2494
references.pmid: 18575617
references.citation: Neuroscience. 2009 Jan 23;158(2):745-50
references.pmid: 19013502
references.citation: Arch Neurol. 2010 Apr;67(4):455-61
references.pmid: 20385912
references.citation: PLoS One. 2011;6(10):e26066
references.pmid: 21998752
references.citation: Neurobiol Dis. 2001 Aug;8(4):581-9
references.pmid: 11493023
references.citation: Muscle Nerve. 2001 Apr;24(4):474-80
references.pmid: 11268018
references.citation: J Biol Chem. 2006 Oct 6;281(40):30152-65
references.pmid: 16847061
references.citation: Neuropathology. 2010 Apr;30(2):182-8
references.pmid: 20102521
references.citation: Neurosci Lett. 2001 Mar 16;300(3):141-4
references.pmid: 11226631
references.citation: Eur J Neurosci. 1998 Aug;10(8):2481-9
references.pmid: 9767379
references.citation: Neurology. 2004 May 25;62(10):1758-65
references.pmid: 15159474
references.citation: Brain. 2008 Jun;131(Pt 6):1540-50
references.pmid: 18469020
references.citation: Acta Neuropathol. 1990;79(4):402-8
references.pmid: 2111074
references.citation: Acta Neuropathol. 1971;19(1):39-50
references.pmid: 4107380
references.citation: Can J Neurol Sci. 1992 Nov;19(4):462-5
references.pmid: 1423043
references.citation: Mol Biol Cell. 2003 Apr;14(4):1610-23
references.pmid: 12686613
references.citation: Mol Biol Cell. 2006 Apr;17(4):1859-70
references.pmid: 16452629
references.citation: Neuropathol Appl Neurobiol. 2011 Jun;37(4):336-52
references.pmid: 21299590
references.citation: J Neurol Neurosurg Psychiatry. 1968 Dec;31(6):535-42
references.pmid: 5709840
references.citation: Exp Neurol. 2007 Feb;203(2):406-14
references.pmid: 17052708
references.citation: Glia. 2001 Mar 15;33(4):277-87
references.pmid: 11246226
references.citation: Brain Res. 2002 Jul 19;944(1-2):195-9
references.pmid: 12106680
references.citation: BMC Neurosci. 2006 Oct 26;7:71
references.pmid: 17067377
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9595-600
references.pmid: 16769894
references.citation: Nat Neurosci. 1999 Jan;2(1):50-6
references.pmid: 10195180
references.citation: Ann Neurol. 1995 Oct;38(4):691-5
references.pmid: 7574472
references.citation: Nature. 2012 Aug 23;488(7412):499-503
references.pmid: 22801503
references.citation: J Neuropathol Exp Neurol. 1998 Oct;57(10):895-904
references.pmid: 9786240
references.citation: Mol Neurobiol. 2003 Aug;28(1):65-106
references.pmid: 14514986
references.citation: Science. 1994 Jun 17;264(5166):1772-5
references.pmid: 8209258
references.citation: Amyotroph Lateral Scler. 2008 Jun;9(3):177-83
references.pmid: 18574762
references.citation: Am J Hum Genet. 2004 Jun;74(6):1128-35
references.pmid: 15106121
references.citation: BMC Neurosci. 2011 Mar 07;12:24
references.pmid: 21385376
references.citation: Glia. 2005 Sep;51(4):241-53
references.pmid: 15846792
references.citation: Exp Neurol. 2006 Mar;198(1):114-28
references.pmid: 16386734
references.citation: Muscle Nerve. 1993 May;16(5):542-7
references.pmid: 8390608
references.citation: Reprod Biomed Online. 2010 Dec;21(6):742-9
references.pmid: 21044866
references.citation: Annu Rev Neurosci. 2004;27:723-49
references.pmid: 15217349
references.citation: Exp Neurol. 2012 Sep;237(1):147-52
references.pmid: 22735487
references.citation: J Clin Invest. 2002 Nov;110(10):1389-98
references.pmid: 12438434
references.citation: Neurology. 1998 Aug;51(2):583-6
references.pmid: 9710040
references.citation: Curr Med Chem. 2007;14(30):3185-200
references.pmid: 18220753
references.citation: Exp Neurol. 1980 Feb;67(2):423-32
references.pmid: 7349996
references.citation: Ann Neurol. 1995 Jul;38(1):73-84
references.pmid: 7611729
references.citation: J Comp Neurol. 2004 Jul 5;474(4):524-34
references.pmid: 15174070
references.citation: Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Jun;1(3):207-12
references.pmid: 11464954
references.citation: Neuroreport. 1999 Nov 8;10(16):3411-6
references.pmid: 10599854
references.citation: J Neurosci Res. 2006 Jan;83(1):134-46
references.pmid: 16323214
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3858-63
references.pmid: 20133711
references.citation: Hum Mol Genet. 2008 Sep 1;17(17):2691-702
references.pmid: 18558633
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):12860-5
references.pmid: 20615984
references.citation: Neurosci Lett. 1994 Sep 26;179(1-2):149-52
references.pmid: 7845611
references.citation: Muscle Nerve. 1981 Sep-Oct;4(5):407-12
references.pmid: 6169987
references.citation: Biochem Biophys Res Commun. 2011 Mar 25;406(4):595-600
references.pmid: 21354103
references.citation: Mamm Genome. 1998 Nov;9(11):893-8
references.pmid: 9799840
references.citation: Q J Exp Physiol. 1982 Oct;67(4):543-55
references.pmid: 7156313
references.citation: Science. 2008 Mar 21;319(5870):1668-72
references.pmid: 18309045
references.citation: J Neurochem. 2002 Apr;81(1):194-202
references.pmid: 12067233
references.citation: Hum Mol Genet. 2003 Oct 1;12(19):2519-32
references.pmid: 12915461
references.citation: Glia. 2009 Sep;57(12):1251-64
references.pmid: 19373940
references.citation: Neuron. 2010 Dec 9;68(5):857-64
references.pmid: 21145000
references.citation: Neuron. 2011 Oct 20;72(2):245-56
references.pmid: 21944778
references.citation: Cell Mol Neurobiol. 1996 Feb;16(1):61-72
references.pmid: 8714560
references.citation: Cereb Cortex. 2011 Mar;21(3):625-35
references.pmid: 20643756
references.citation: J Proteome Res. 2009 Nov;8(11):5229-40
references.pmid: 19764823
references.citation: J Neurosci. 2006 Nov 8;26(45):11798-806
references.pmid: 17093100
references.citation: Acta Neuropathol. 2007 May;113(5):535-42
references.pmid: 17333220
references.citation: Genomics. 1992 May;13(1):39-43
references.pmid: 1349581
references.citation: Neurobiol Dis. 2004 Mar;15(2):340-50
references.pmid: 15006704
references.citation: Science. 1994 Aug 19;265(5175):1107-10
references.pmid: 8066451
references.citation: Neurol Res Int. 2012;2012:806306
references.pmid: 22919484
references.citation: Science. 2009 Feb 27;323(5918):1205-8
references.pmid: 19251627
references.citation: J Neurochem. 2002 Feb;80(4):616-25
references.pmid: 11841569
references.citation: Am J Pathol. 1974 Jul;76(1):63-78
references.pmid: 4367129
references.citation: Brain Res. 1987 Feb 24;404(1-2):127-32
references.pmid: 3567560
references.citation: Neurobiol Dis. 2010 Mar;37(3):493-502
references.pmid: 19833209
references.citation: Brain Res. 1992 May 15;580(1-2):303-10
references.pmid: 1504807
references.citation: J Cell Sci. 2004 Jun 1;117(Pt 13):2791-804
references.pmid: 15150321
references.citation: J Neurochem. 2006 Mar;96(5):1349-61
references.pmid: 16478527
references.citation: Neurochem Res. 2002 Mar;27(3):225-8
references.pmid: 11958520
references.citation: Brain Pathol. 2010 Mar;20(2):351-60
references.pmid: 19338576
references.citation: Biol Reprod. 2010 May;82(5):930-9
references.pmid: 20130268
references.citation: Neurosci Lett. 2002 Sep 6;329(3):334-8
references.pmid: 12183043
references.citation: Neurobiol Dis. 2008 Mar;29(3):465-76
references.pmid: 18201889
references.citation: J Reprod Fertil. 1980 Jan;58(1):267-70
references.pmid: 7359484
references.citation: Muscle Nerve. 1996 Jun;19(6):797-8
references.pmid: 8609941
references.citation: Science. 2003 Oct 3;302(5642):113-7
references.pmid: 14526083
references.citation: Neurochem Int. 2009 Sep;55(5):302-6
references.pmid: 19576518
references.citation: Brain Res. 2002 Mar 15;930(1-2):53-7
references.pmid: 11879795
references.citation: Neurodegeneration. 1995 Jun;4(2):209-16
references.pmid: 7583686
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15558-63
references.pmid: 18809917
references.citation: J Neurosci Res. 1997 Apr 1;48(1):63-70
references.pmid: 9086182
references.citation: Acta Neuropathol. 2013 Feb;125(2):273-88
references.pmid: 22961620
references.citation: Lancet Neurol. 2010 Oct;9(10):995-1007
references.pmid: 20864052
references.citation: Neurobiol Dis. 2008 Jun;30(3):400-407
references.pmid: 18440237
references.citation: Nat Neurosci. 2002 Apr;5(4):301-7
references.pmid: 11889469
references.citation: Neuroscience. 2003;120(1):113-20
references.pmid: 12849745
references.citation: Acta Physiol (Oxf). 2010 Dec;200(4):361-76
references.pmid: 20874803
references.citation: Nat Genet. 2005 Nov;37(11):1213-5
references.pmid: 16244655
references.citation: Ann Neurol. 2011 Dec;70(6):913-9
references.pmid: 21842496
references.citation: Neurobiol Dis. 2004 Nov;17(2):349-57
references.pmid: 15474372
references.citation: J Cell Biol. 1999 Nov 1;147(3):531-44
references.pmid: 15132161
references.citation: Nature. 2005 Jan 6;433(7021):73-7
references.pmid: 15635412
references.citation: Cell. 1993 Apr 9;73(1):35-46
references.pmid: 8462101
references.citation: Muscle Nerve. 1995 Nov;18(11):1344-7
references.pmid: 7565937
references.citation: Neurobiol Dis. 2002 Dec;11(3):457-68
references.pmid: 12586554
references.citation: Exp Neurol. 2010 Sep;225(1):163-72
references.pmid: 20558160
references.citation: PLoS One. 2010 Oct 11;5(10):e13250
references.pmid: 20948999
references.citation: Neuroreport. 2001 Jul 3;12(9):1815-20
references.pmid: 11435904
references.citation: Eur J Neurol. 2009 Jun;16(6):771-4
references.pmid: 19236470
references.citation: J Neurochem. 2009 Feb;108(4):973-985
references.pmid: 19183264
references.citation: Neurology. 2006 Sep 26;67(6):1074-7
references.pmid: 16807408
references.citation: EMBO J. 2010 Aug 18;29(16):2841-57
references.pmid: 20606625
references.citation: Brain. 1982 Dec;105 (Pt 4):811-34
references.pmid: 7139256
references.citation: Cell Stem Cell. 2008 Dec 4;3(6):637-48
references.pmid: 19041780
references.citation: PLoS One. 2012;7(2):e32326
references.pmid: 22384217
references.citation: Am J Hum Genet. 2003 Aug;73(2):397-403
references.pmid: 12858291
references.citation: Nature. 1993 Jul 22;364(6435):362
references.pmid: 8332197
references.citation: J Cell Biol. 2000 Jul 10;150(1):165-76
references.pmid: 10893265
references.citation: Am J Hum Genet. 2002 Jan;70(1):251-6
references.pmid: 11706389
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20523-8
references.pmid: 21059924
references.citation: Clin Med (Lond). 2010 Jun;10(3):252-8
references.pmid: 20726457
references.citation: Nat Rev Neurol. 2011 Nov;7(11):616-30
references.pmid: 22051914
references.citation: Brain Res Bull. 1999 Mar 1;48(4):429-39
references.pmid: 10357076
references.citation: Nat Neurosci. 2007 May;10(5):615-22
references.pmid: 17435755
references.citation: Brain Res. 1991 Jun 14;551(1-2):142-4
references.pmid: 1913146
references.citation: Cell. 1993 Apr 9;73(1):23-33
references.pmid: 8462100
references.citation: J Biol Chem. 2011 Jul 1;286(26):23432-40
references.pmid: 21518771
references.citation: Neuropathol Appl Neurobiol. 1993 Aug;19(4):291-9
references.pmid: 8232749
references.citation: Hum Mol Genet. 2007 Oct 1;16(19):2359-65
references.pmid: 17636250
references.citation: Amyotroph Lateral Scler. 2009 Oct-Dec;10(5-6):405-9
references.pmid: 19922131
references.citation: Dev Dyn. 1997 Jul;209(3):286-95
references.pmid: 9215643
references.citation: Genomics. 1997 Jul 15;43(2):242-4
references.pmid: 9244444
references.citation: Brain Res. 2004 Sep 3;1019(1-2):226-36
references.pmid: 15306257
references.citation: Exp Neurol. 2009 Nov;220(1):177-82
references.pmid: 19716820
references.citation: J Cell Biol. 2004 May 10;165(3):347-56
references.pmid: 15123740
references.citation: Mol Biol Cell. 2000 Jan;11(1):305-23
references.pmid: 10637310
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16325-30
references.pmid: 20736350
references.citation: J Cell Biol. 2002 Nov 25;159(4):563-9
references.pmid: 12446740
references.citation: Ann Neurol. 2011 Jan;69(1):152-62
references.pmid: 21280085
references.citation: J Neuropathol Exp Neurol. 2007 Jan;66(1):10-6
references.pmid: 17204932
references.citation: PLoS Genet. 2010 Mar 26;6(3):e1000887
references.pmid: 20361056
references.citation: Mol Med. 2012 May 09;18:401-11
references.pmid: 22076467
references.citation: Neuropathol Appl Neurobiol. 2003 Dec;29(6):529-45
references.pmid: 14636160
references.citation: J Neuropathol Exp Neurol. 1984 Sep;43(5):461-70
references.pmid: 6540799
references.citation: Rejuvenation Res. 2011 Dec;14(6):623-39
references.pmid: 21978082
references.citation: J Cell Biol. 2003 Nov 24;163(4):755-66
references.pmid: 14638859
references.citation: Brain Res. 1996 Jul 8;726(1-2):91-7
references.pmid: 8836549
references.citation: Brain Res. 2001 Oct 26;917(1):97-104
references.pmid: 11602233
references.citation: J Neurocytol. 1990 Feb;19(1):29-38
references.pmid: 2351995
references.citation: Amyotroph Lateral Scler Other Motor Neuron Disord. 2005 Jun;6(2):100-3
references.pmid: 16036433
references.citation: Neurogenetics. 1998 Dec;2(1):55-60
references.pmid: 9933301
references.citation: J Neurol Sci. 1998 Oct;160 Suppl 1:S106-13
references.pmid: 9851659
references.citation: J Neurol Sci. 1998 Sep 18;160(1):9-15
references.pmid: 9804111
references.citation: Nature. 2010 May 13;465(7295):223-6
references.pmid: 20428114
references.citation: Exp Neurol. 2007 May;205(1):74-81
references.pmid: 17362932
references.citation: Nat Genet. 2002 Nov;32(3):443-7
references.pmid: 12389029
references.citation: Ann Neurol. 1997 Aug;42(2):200-7
references.pmid: 9266730
references.citation: Muscle Nerve. 2001 Jun;24(6):769-77
references.pmid: 11360260
references.citation: Lancet. 2007 Jun 16;369(9578):2031-2041
references.pmid: 17574095
references.citation: Am J Physiol Regul Integr Comp Physiol. 2011 Apr;300(4):R844-54
references.pmid: 21248309
references.citation: Nat Neurosci. 2009 May;12(5):627-36
references.pmid: 19330001
references.citation: Arch Neurol. 2010 Feb;67(2):224-30
references.pmid: 20142531
references.citation: Brain Res. 1979 Jun 29;169(3):443-54
references.pmid: 445165
references.citation: Neurology. 2012 May 15;78(20):1596-600
references.pmid: 22517106
references.citation: Ann Neurol. 1998 Oct;44(4):696-9
references.pmid: 9778272
references.citation: Neuron. 1995 Jun;14(6):1105-16
references.pmid: 7605627
references.citation: Nat Genet. 2001 Oct;29(2):160-5
references.pmid: 11586297
references.citation: Lancet Neurol. 2011 Mar;10(3):253-63
references.pmid: 21349440
references.citation: Muscle Nerve. 1990 Feb;13(2):121-6
references.pmid: 2314413
references.citation: Am J Hum Genet. 2009 Jan;84(1):85-8
references.pmid: 19118816
references.citation: Hum Mol Genet. 2010 Feb 15;19(4):671-83
references.pmid: 19959528
references.citation: J Neuropathol Exp Neurol. 1997 May;56(5):459-71
references.pmid: 9143258
references.citation: Neuroscience. 1999;93(2):565-72
references.pmid: 10465440
references.citation: J Biol Chem. 2010 Dec 17;285(51):40266-81
references.pmid: 20940299
references.citation: Exp Cell Res. 2005 May 15;306(1):24-34
references.pmid: 15878329
references.citation: Cell Rep. 2012 Nov 29;2(5):1363-74
references.pmid: 23142660
references.citation: Brain Res. 2000 Mar 6;858(1):84-91
references.pmid: 10700601
references.citation: Spermatogenesis. 2011 Jan;1(1):52-62
references.pmid: 21866276
references.citation: Exp Neurol. 2005 Oct;195(2):518-23
references.pmid: 16095593
references.citation: Science. 2006 Oct 6;314(5796):130-3
references.pmid: 17023659
references.citation: Ann Neurol. 1986 Jan;19(1):36-43
references.pmid: 3947038
references.citation: Neurochem Res. 1999 Jan;24(1):1-8
references.pmid: 9973230
references.citation: J Biol Chem. 2002 Aug 16;277(33):29626-33
references.pmid: 12050154
references.citation: Biol Reprod. 2005 Jan;72(1):14-21
references.pmid: 15342353
references.citation: Hum Mol Genet. 2007 Nov 15;16(22):2720-2728
references.pmid: 17725983
references.citation: J Neurochem. 2012 Jul;122(1):185-95
references.pmid: 22486171
references.citation: Acta Neuropathol. 2010 Apr;119(4):409-19
references.pmid: 20198480
references.citation: Brain Res Mol Brain Res. 1996 Jun;38(2):267-75
references.pmid: 8793115