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Animal models of MND
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RelatedMotor Neurone Disease

Animal models of neurodegeneration are an invaluable tool for studying the pathogenic mechanisms involved in vivo at all stages of the disease, even before symptom onset. Murine models of MND in particular are used to study the cellular and molecular pathways involved, as such pathways are usually highly conserved between mouse and human (Hafezparast et al., 2003a). A selection of the most widely used mouse models are described below. Other animal models of MND include mutant SOD1 rats (Howland et al., 2002) and survival motor neuron (SMN) knockdown zebrafish (McWhorter et al., 2003).

Transgenic mice have been created to investigate the function of proteins already known or suspected to be involved in MND, such as SOD1 and neurofilaments (NFs). This is known as a ‘genotype driven’ approach. In contrast, mice have been found (‘natural/spontaneous mutants’) or created (by the use of irradiation or chemical mutagens) that exhibit a MND pathology, in a ‘phenotype driven’ approach. The causal gene has been identified in many of these mice and this has brought useful information regarding the proteins and pathways involved in motor neuron degeneration.

Spontaneous mutants

Wobbler mouse

The Wobbler mouse has an unsteady gait with progressive weakness, typically dying by 3 months of age (Duchen and Strich, 1968), and is often used as a model of MND. However, recent studies have suggested that the disease in Wobbler mice may be a more generalised neurodegeneration than MND, as degeneration is seen in the thalamus, cerebellum and brainstem, and this precedes degeneration of the motor neurons and onset of gliosis (Rathke-Hartlieb et al., 1999). The gene mutated in this autosomal recessive disease model is not yet known but has been mapped to chromosome 11 (Kaupmann et al., 1992).

Progressive motor neuronopathy (pmn) mouse

The progressive motor neuronopathy (pmn) mutant mouse is a widely used model of MND (most closely resembling SMA) that develops hind-limb paralysis and displays progressive degeneration of motor neurons until death occurs in the early postnatal period (6-8 weeks) (Schmalbruch et al., 1991). The autosomal recessive mutation causing this pathology was originally mapped to chromosome 13 (Brunialti et al., 1995) and has been subsequently identified as a point mutation in the tubulin-specific chaperone E (Tbce) gene (Bommel et al., 2002; Martin et al., 2002). Tbce encodes the protein cofactor E (CofE) which is a tubulin-specific chaperone and is essential in the correct assembly of microtubules (Bommel et al., 2002; Martin et al., 2002). This discovery is extremely interesting as defects of microtubule function and impairment of axonal transport have been extensively implicated in pathogenic mechanisms of MND.

ENU-induced mutants

N-Ethyl-N-nitrosurea (ENU) is a chemical mutagen that produces point mutations in the genome, which enables identification of the causal gene by methods such as ‘positional candidate cloning’, and is currently being used to generate new mouse models of MND (Brown and Balling, 2001; Chen et al., 2000; Hafezparast et al., 2003a). So far, this approach has successfully created the mouse Legs at odd angles (Loa) which develops a late onset progressive motor neuron disease with neuropathological features similar to those seen in other MND mouse models, including mitochondrial swelling, Golgi fragmentation and cytoplasmic inclusions (Hafezparast et al., 2003a; Rogers et al., 2001). The causal mutation in the Loa mouse is inherited in an autosomal dominant fashion, and has been found to occur in the cytoplasmic dynein heavy chain gene Dnchc1, which suggests involvement of the dynein-dynactin complex in MND. Furthermore, a different mutation in dynein heavy chain has been identified in a second ENU mutagenesis-generated mouse, Cramping1 (Cra1).

Targeted mutants

SOD1 transgenic mice

SOD1 is a ubiquitous enzyme and is highly expressed in motor neurons (Pardo et al., 1995). The primary function of SOD1 within the cell is to catalyse the conversion (dismutation) of superoxide radicals (by-products of normal cellular metabolism) to hydrogen peroxide, which is then eliminated by other free radical-scavenging enzymes (glutathione peroxidase and catalase). It also has other activities in the cell including peroxidase activity (resulting in generation of hydroxyl radicals from hydrogen peroxide or superoxide, or production of nitronium species from peroxynitrite) and protection of the enzyme calcineurin from inactivation (Hodgson and Fridovich, 1975; Wang et al., 1996). Transgenic mice carrying the human SOD1 mutants found in FALS (the most widely-used mutants are G37R, G85R, G93A, G93R) on a wild-type mouse SOD1 background develop progressive muscle weakness and atrophy and have a pathology that highly resembles the human disease, including loss of motor neurons and interneurons, reactive astrocytosis, and inclusion bodies immunoreactive for ubiquitin, neurofilaments and SOD1 (Bruijn et al., 1997b; Cha et al., 1998; Dal Canto and Gurney, 1995; Gonatas et al., 1998; Gurney et al., 1994; Kong and Xu, 1998; Mourelatos et al., 1996; Tu et al., 1996; Wong and Borchelt, 1995; Zhang et al., 1997). Mice with high copy numbers (high expresser mice) show early onset of disease, whereas mice with low copy numbers (low expresser mice) are affected by a late-onset disease (Dal Canto and Gurney, 1997), and the type of mutation seems to affect the severity/rapidity of progression (Gurney, 1997; Shibata, 2001).

SOD1 mutant mouse models have therefore been widely used to study the molecular and cellular processes occurring both before disease onset and during disease progression. It is believed that such research may lead to identification of therapeutic targets and/or elucidation of the neurodegenerative mechanisms involved in all forms of MND. The use of mutant SOD1 mice has enabled the identification of pre-symptomatic neuropathology such as fragmentation of the Golgi apparatus and mitochondrial vacuolation (Dal Canto and Gurney, 1995; Mourelatos et al., 1996; Wong and Borchelt, 1995), and biological processes disrupted before and during disease progression such as axonal transport (Borchelt et al., 1998; Warita et al., 1998; Williamson and Cleveland, 1999; Zhang et al., 1997).

The means by which SOD1 exerts its toxicity is unknown, although it is thought to occur by a ‘gain of toxic function’ rather than loss of the dismutase activity of the protein. This is supported by several findings from the study of mutant SOD1 mice, including: SOD1 wild-type knockout mice do not develop a disease pathology (although they display subtle motor defects and their motor neurons show an increased sensitivity to axonal injury) (Reaume et al., 1996); the toxicity of mutant SOD1 is not accelerated or reduced by loss of wild-type SOD1 in transgenic mutant SOD1 mice (Bruijn et al., 1998), and is either unaffected (Bruijn et al., 1998) or enhanced (Jaarsma et al., 2000) by increasing wild-type SOD1 activity; some mutants still cause disease despite retaining their dismutase activity (Borchelt et al., 1994; Bowling et al., 1993).

Neurofilament and peripherin mouse models

Neurofilaments are type IV intermediate filament (IF) proteins that are a major component of the neuronal cytoskeleton, and are composed of 3 subunits that range in size according to the size of their tail domain; neurofilament light chain (NF-L; 68 kDa), neurofilament medium chain (NF-M; 95 kDa), neurofilament heavy chain (NF-H; 110 kDa). They are responsible for the maintenance of neuronal calibre and are particularly abundant in large myelinated neurons, such as those that are preferentially affected in MND, and are found in filamentous inclusions in spinal cord motor neurons of MND post-mortem tissue. Peripherin, a type III neuronal IF protein, is also found in the majority of motor neuron neurofilament inclusions in MND, although its expression is usually (in non-disease cases) most abundant in autonomic nerves and peripheral sensory neurons, with low levels in spinal motor neurons (Escurat et al., 1990; Parysek and Goldman, 1988; Troy et al., 1990a; Troy et al., 1990b). The discovery of intermediate filament inclusions in MND has led to the proposal that they are involved in the pathogenesis of the disease, and so transgenic mouse models have been created to investigate this possibility. Transgenic mice overexpressing human NF-H (Cote et al., 1993), mouse NF-L (Xu et al., 1993) or mouse peripherin (Beaulieu et al., 1999) all develop an MND-like pathology with muscle atrophy, reduced axonal calibre and IF inclusions. This has led to extensive research into the role of IF proteins in the disease mechanisms that cause MND.

Mutant VEGF mice

Mice carrying a targeted deletion of the hypoxia response element (HRE) within the vascular endothelial growth factor (VEGF) promoter have a phenotype similar to that of human ALS (Oosthuyse et al., 2001). This has led to the proposal that this gene may be involved in ALS, although linkage studies have as yet failed to support this hypothesis (Gros-Louis et al., 2003a). The mechanism by which the mouse phenotype occurs is unknown, although it has been proposed that motor neuron death could occur due to reduced perfusion under low oxygen conditions (with motor neurons being particularly vulnerable due to their large size and high energy/oxygen requirements), and/or VEGF could have neuroprotective effects on motor neurons under normal circumstances (Oosthuyse et al., 2001). Indeed, treatment with VEGF has been found to protect motor neurons against cell death following spinal cord ischemia in mice (Lambrechts et al., 2003) and in a mutant SOD1 rat model (Storkebaum et al., 2005).

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