**6. References**


Dynamic Meta-Analysis as a Therapeutic Prediction Tool for Amyotrophic Lateral Sclerosis 79

Kuo, J. J., M. Schonewille, et al. (2004). "Hyperexcitability of cultured spinal motoneurons

Kuo, J. J., T. Siddique, et al. (2005). "Increased persistent Na(+) current and its effect on

Mattson, M. P. and W. Duan (1999). "Apoptotic" biochemical cascades in synaptic

Meyer, M. A. and N. T. Potter (1995). "Sporadic ALS and chromosome 22: evidence for a

Miller, R. G., J. D. Mitchell, et al. (2007). "Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)." *Cochrane Database Syst Rev*(1): CD001447. Mitchell, C. S. (2009). Viewpoint aggregation via relational modeling and analysis: A new

excitability in motoneurones cultured from mutant SOD1 mice." *J Physiol* 563(Pt 3):

compartments: roles in adaptive plasticity and neurodegenerative disorders." *J* 

approach to systems physiology. *Wallace H. Coulter Department of Biomedical Engineering*. Atlanta, GA, Georgia Institute of Technology and Emory University. Mitchell, C. S., S. S. Feng, et al. (2007). "An analysis of glutamate spillover on the N-methyl-D-aspartate receptors at the cerebellar glomerulus." *J Neural Eng* 4(3): 276-282. Mitchell, C. S. and R. H. Lee (2007). "Output-based comparison of alternative kinetic

schemes for the NMDA receptor within a glutamate spillover model." *J Neural Eng*

*Pathology dynamics and combination treatment predictions*. 21st International

enzyme in spinal motor neurons of presymptomatic transgenic mice that express a

growth factor-1 associating with the signal transduction systems in SODG93A

factor erythroid 2-related factor 2 activation in p75 neurotrophin receptor-induced

recent advances from the transgenic mutant SOD1 mice." *CNS Neurol Disord Drug* 

superoxide dismutase in motor neurons by postsynaptic calcium-dependent

Mitchell, C. S. and R. H. Lee (2008). "Pathology dynamics predict spinal cord injury

Mitchell, C. S. and R. H. Lee (2009). "A quantitative examination of the role of cargo-exerted

Mitchell, C. S. and R. H. Lee (2010). *Dynamic Meta-Analysis of the G93A SOD1 mouse model:* 

Nagai, M., D. B. Re, et al. (2007). "Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons." *Nat Neurosci* 10(5): 615-622. Nagano, I., T. Murakami, et al. (2002). "Early decrease of survival factors and DNA repair

Narai, H., I. Nagano, et al. (2005). "Prevention of spinal motor neuron death by insulin-like

Pastula, D. M., D. H. Moore, et al. (2010). "Creatine for amyotrophic lateral sclerosis/motor

Pehar, M., M. R. Vargas, et al. (2007). "Mitochondrial superoxide production and nuclear

Peviani, M., I. Caron, et al. "Unraveling the complexity of amyotrophic lateral sclerosis:

Rothstein, J. D. (2009). "Current hypotheses for the underlying biology of amyotrophic

Roy, J., S. Minotti, et al. (1998). "Glutamate potentiates the toxicity of mutant Cu/Zn-

therapeutic success." *J Neurotrauma* 25(12): 1483-1497.

forces in axonal transport." *J Theor Biol* 257(3): 430-437.

Symposium on ALS/MND, Orlando, FL.

mutant SOD1 gene." *Life Sci* 72(4-5): 541-548.

transgenic mice." *J Neurosci Res* 82(4): 452-457.

lateral sclerosis." *Ann Neurol* 65 Suppl 1: S3-9.

mechanisms." *J Neurosci* 18(23): 9673-9684.

neuron disease." *Cochrane Database Syst Rev*(6): CD005225.

motor neuron apoptosis." *J Neurosci* 27(29): 7777-7785.

from presymptomatic ALS mice." *J Neurophysiol* 91(1): 571-575.

possible neurofilament gene defect." *Muscle Nerve* 18(5): 536-539.

843-854.

4(4): 380-389.

*Targets* 9(4): 491-503.

*Neurosci Res* 58(1): 152-166.


De Vos, K. J., A. L. Chapman, et al. (2007). "Familial amyotrophic lateral sclerosis-linked

Derave, W., L. Van Den Bosch, et al. (2003). "Skeletal muscle properties in a transgenic

Dobrowolny, G., M. Aucello, et al. (2008). "Skeletal muscle is a primary target of

Dunlop, J., H. Beal McIlvain, et al. (2003). "Impaired spinal cord glutamate transport

Echaniz-Laguna, A., J. Zoll, et al. (2002). "Mitochondrial respiratory chain function in

Gifondorwa, D. J., M. B. Robinson, et al. (2007). "Exogenous delivery of heat shock protein

Gould, T. W., R. R. Buss, et al. (2006). "Complete dissociation of motor neuron death from

Guatteo, E., I. Carunchio, et al. (2007). "Altered calcium homeostasis in motor neurons

Hall, E. D., P. K. Andrus, et al. (1998). "Relationship of oxygen radical-induced lipid

Hayward, L. J., J. A. Rodriguez, et al. (2002). "Decreased metallation and activity in subsets

Ikonomidou, C., Y. Qin Qin, et al. (1996). "Motor neuron degeneration induced by

Kadoyama, K., H. Funakoshi, et al. (2007). "Hepatocyte growth factor (HGF) attenuates

Kieran, D., M. Hafezparast, et al. (2005). "A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice." *J Cell Biol* 169(4): 561-567. King, A. E., T. C. Dickson, et al. (2009). "Neuron-glia interactions underlie ALS-like axonal

Kong, J. and Z. Xu (1998). "Massive mitochondrial degeneration in motor neurons triggers

transgenic mouse model of ALS." *Neurosci Res* 59(4): 446-456.

content." *Hum Mol Genet* 16(22): 2720-2728.

SOD1G93A-mediated toxicity." *Cell Metab* 8(5): 425-436.

model." *Proc Natl Acad Sci U S A* 101(30): 11159-11164.

skeletal muscle of ALS patients." *Ann Neurol* 52(5): 623-627.

*Neurobiol Dis* 13(3): 264-272.

27(48): 13173-13180.

*Disord* 4(4): 249-257.

55(2): 211-224.

familial ALS." *J Neurosci Res* 53(1): 66-77.

sclerosis." *J Biol Chem* 277(18): 15923-15931.

cytoskeletal pathology." *Neurobiol Aging*.

*Neurosci* 18(9): 3241-3250.

8774-8786.

SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria

mouse model for amyotrophic lateral sclerosis: effects of creatine treatment."

capacity and reduced sensitivity to riluzole in a transgenic superoxide dismutase mutant rat model of amyotrophic lateral sclerosis." *J Neurosci* 23(5): 1688-1696. Dupuis, L., H. Oudart, et al. (2004). "Evidence for defective energy homeostasis in

amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse

70 increases lifespan in a mouse model of amyotrophic lateral sclerosis." *J Neurosci*

motor dysfunction by Bax deletion in a mouse model of ALS." *J Neurosci* 26(34):

following AMPA receptor but not voltage-dependent calcium channels' activation in a genetic model of amyotrophic lateral sclerosis." *Neurobiol Dis* 28(1): 90-100. Hafezparast, M., A. Ahmad-Annuar, et al. (2003). "Paradigms for the identification of new

genes in motor neuron degeneration." *Amyotroph Lateral Scler Other Motor Neuron* 

peroxidative damage to disease onset and progression in a transgenic model of

of mutant superoxide dismutases associated with familial amyotrophic lateral

excitotoxin agonists has features in common with those seen in the SOD-1 transgenic mouse model of amyotrophic lateral sclerosis." *J Neuropathol Exp Neurol*

gliosis and motoneuronal degeneration in the brainstem motor nuclei of a

the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1." *J* 


**4** 

*Canada* 

*In Vivo* **and** *In Vitro* **Models to** 

François Berthod and François Gros-Louis

*Centre LOEX de l'Université Laval,* 

**Study Amyotrophic Lateral Sclerosis** 

*Centre de recherche FRSQ du Centre hospitalier affilié universitaire de Québec, Département de Chirurgie, Faculté de Médecine, Université Laval, Québec,* 

Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset neurodegenerative disorder characterized by the death of large motor neurons in the cerebral cortex and spinal cord (Tandan and Bradley, 1985). Dysfunction and death of these cell populations lead to progressive muscle weakness, atrophy, fasciculations, spasticity and ultimately, paralysis and death usually within 3 to 5 years after disease onset (Mulder, 1982). The estimated worldwide incidence for this disease is around 2 per 100,000 in the general population and the life-long risk to develop ALS is approximately 1:2000. The disease occurs in sporadic (90%) and familial forms (10%) (Gros-Louis, et al., 2006). With the exception of few FALS cases in which other neurodegenerative disorders can simultaneously occur, FALS and SALS are clinically indistinguishable. To date, mutations in the Cu/Zn superoxide dismutase 1 (*SOD1*) gene have remained the major known genetic causes associated with ALS. However, the mechanism whereby mutant SOD1 causes specific degeneration of motor neurons remains unclear. Nonetheless, many neuronal death pathways have been revealed through studies with transgenic mice expressing SOD1 mutants. Other vertebrate, invertebrate and *in vitro* models of ALS have also been described. Here, we will review various animal and cellular models that have been used to study the toxicity of ALS-linked

gene mutations and also to investigate pathological hallmarks of the disease.

Though most cases of ALS are sporadic, 10% of cases have affected relatives, some with clear Mendelian inheritance and high penetrance (Gros-Louis, et al., 2006). The landmark discovery in 1993 of missense mutations in the *SOD1* gene in subsets of familial cases directed most ALS research to elucidate the mechanism of SOD1-mediadted disease (Rosen, et al., 1993). More recently, mutations in two other genes, *TARDBP* and *FUS/TLS* have been found in ALS patients (Kabashi, et al., 2008; Sreedharan, et al., 2008; Vance, et al., 2009). Rare mutations in other genes such as *ANG*, *ALS2*, *DCTN1*, *MAPT*, *SETX* and *VAPB* have also been described (for reviews see (Gros-Louis, et al., 2006)). Various other genetic mutations in the *ELP3* ((Simpson, et al., 2009), *FIG4* (Chow, et al., 2009), *DAO* (Mitchell, et al., 2010), *OPTN* (Maruyama, et al., 2010) and *CHGB* (Gros-Louis, et al., 2009a) genes have also been

**1. Introduction** 

**1.1 Familial ALS** 

