Pre-symptomatic detection of chronic motor deficits and genotype prediction in congenic B6.SOD1(G93A) ALS mouse model.
Amyotrophic lateral sclerosis (ALS) is an incurable progressive paralytic motor neuron disease with limited therapeutic options. Since their creation by Gurney et al. (1994) [Science 264:1772-1775], transgenic superoxide dismutase-1 with glycine to alanine switch at codon 93 (SOD1(G93A)) mice have become the benchmark pre-clinical model for screening ALS therapies. Surprisingly, despite physiological, anatomical, ultrastructural and biochemical evidence of early motor system dysfunction, it has proven difficult to detect motor performance deficits in pre-symptomatic SOD1(G93A) mice. As an alternative to conventional forced motor tests, we investigated the progression of motor performance deficits in freely behaving pre-symptomatic congenic B6.SOD1(G93A) mice. We found that motor performance deficits began several weeks prior to the onset of overt clinical symptoms (postnatal day 45). More importantly, once motor performance deficits manifested, they persisted in parallel with disease progression. In addition, two physical measures of muscle girth revealed progressive hindlimb muscle atrophy that predicted genotype in individual pre-symptomatic mice with 80% accuracy. Together, these data suggest that muscle girth is a reliable and indirect measure of hindlimb muscle denervation and an early, objective marker for disease onset in congenic B6.SOD1(G93A) ALS mice. Moreover, we present regression equations based on hindlimb muscle girth for predicting genotype in future studies using B6.SOD1(G93A) mice. These findings support new objective criteria for clinical disease onset and provide objective measures that require little expertise. These studies demonstrate a cost-effective approach for more thorough evaluation of neuroprotective strategies that seek to disrupt disease mechanisms early in the disease process. To our knowledge, these findings are the first to report early chronic motor performance and physical deficits that are coincident with the earliest known motor dysfunction in any ALS mouse model.
Hayworth
C R
CR
Department of Psychology, Institute for Neuroscience, University of Texas at Austin, 2701 Speedway, Austin, TX 78712, USA. roymontana@mail.utexas.edu
Gonzalez-Lima
F
F
D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D042241:Early Diagnosis; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006614:Hindlimb / Q000294:innervation / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D009069:Movement Disorders / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D018908:Muscle Weakness / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000294:innervation / Q000503:physiopathology; D009460:Neurologic Examination; D011237:Predictive Value of Tests; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
D005819:Genetic Markers; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
Muscle Nerve. 2005 Jul;32(1):43-50
15880561
J Neurol Sci. 2005 Sep 15;236(1-2):1-7
16024047
Neuroscience. 2008 Jan 24;151(2):613-21
18061359
Neuroreport. 1999 Apr 6;10(5):1013-8
10321477
Exp Neurol. 2009 Mar;216(1):3-6
19084005
Muscle Nerve. 1997 Feb;20(2):179-85
9040656
Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):2007-11
19174508
Nat Neurosci. 2006 Mar;9(3):408-19
16474388
Growth Factors. 2009 Jun;27(3):133-40
19294549
J Mot Behav. 2008 Nov;40(6):568-77
18980909
Neurobiol Dis. 2008 Mar;29(3):400-8
18054242
Neurosci Lett. 2006 Mar 6;395(2):103-7
16356650
Ann Neurol. 2003 Jun;53(6):804-7
12783429
Muscle Nerve. 1991 May;14(5):416-21
1870632
J Neurosci. 2005 Jan 5;25(1):164-72
15634778
Science. 1994 Jun 17;264(5166):1772-5
8209258
Mol Cell Neurosci. 1995 Aug;6(4):349-62
8846004
Mayo Clin Proc. 1976 Sep;51(9):537-41
957788
J Comp Neurol. 2005 Sep 26;490(3):209-19
16082680
Neurobiol Dis. 2007 Nov;28(2):154-64
17766128
J Neurol Sci. 2005 Aug 15;235(1-2):61-8
15990113
Neurology. 2001 Nov 27;57(10):1857-61
11723276
J Neurosci. 2006 Aug 23;26(34):8774-86
16928866
Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4465-70
19251638
J Neurochem. 2005 May;93(4):875-82
15857390
Eur J Neurosci. 2004 Nov;20(10):2822-6
15548226
J Neurosci. 2000 Apr 1;20(7):2534-42
10729333
Amyotroph Lateral Scler Other Motor Neuron Disord. 2005 Mar;6(1):55-62
16036427
Exp Neurol. 2004 Feb;185(2):232-40
14736504
J Appl Physiol (1985). 2007 Mar;102(3):926-32
17110520
J Neurobiol. 2003 Mar;54(4):566-76
12555269
Prog Neurobiol. 2008 May;85(1):94-134
18282652
J Physiol Paris. 2006 Mar-May;99(2-3):211-20
16448809
Neurobiol Dis. 2006 Jun;22(3):599-610
16616851
Adv Neurol. 1982;36:15-22
7180681
Brain Res. 2003 Aug 22;982(1):92-7
12915243
Nature. 2004 May 27;429(6990):413-7
15164063
Neuroreport. 1996 May 31;7(8):1427-31
8856691
Science. 2006 Jun 2;312(5778):1389-92
16741123
Neuron. 1995 Jan;14(1):133-41
7826631
Ann Neurol. 1996 Feb;39(2):203-16
8967752
Proc Natl Acad Sci U S A. 1996 May 28;93(11):5472-7
8643599
J Neurosci. 1998 May 1;18(9):3241-50
9547233
Cytotherapy. 2007;9(5):414-26
17786603
Eur J Neurosci. 2007 Mar;25(6):1669-77
17432958
Neuron. 1995 Jun;14(6):1105-16
7605627
J Neurocytol. 2003 Jun-Sep;32(5-8):975-85
15034280
Neurobiol Dis. 2007 Apr;26(1):146-52
17276077
Neuron. 1995 Jan;14(1):125-32
7826630
Neuroreport. 2003 May 23;14(7):1051-4
12802201
J Neurosci. 1999 Dec 15;19(24):RC46
10594090
Neuromuscul Disord. 2003 Nov;13(9):737-43
14561497