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Animal Models for Motor Neuron Disease Laboratory Animal Science Vol 49, No 5 Copyright 1999 October 1999 by the American Association for Laboratory Animal Science Special Topic Overview Animal Models for Motor Neuron Disease Sherril L. Green and Ravi J. Tolwani* Abstract: Motor neuron disease is a general term applied to a broad class of neurodegenerative diseases that are characterized by fatally progressive muscular weakness, atrophy, and paralysis attributable to loss of motor neurons. At present, there is no cure for most motor neuron diseases, including amyotrophic lateral sclerosis (ALS), the most common human motor neuron disease—the cause of which remains largely unknown. Animal models of motor neuron disease (MND) have significantly contributed to the remarkable recent progress in understanding the cause, genetic factors, and pathologic mechanisms proposed for this class of human neurodegenerative disorders. Largely driven by ALS research, animal models of MND have proven their use- fulness in elucidating potential causes and specific pathogenic mechanisms, and have helped to advance promising new treatments from “benchside to bedside.” This review summarizes important features of se- lected established animal models of MND: genetically engineered mice and inherited or spontaneously occur- ring MND in the murine, canine, and equine species. The term “motor neuron disease” (MND) is used to designate Table 1. General classification of selected common human motor a variety of neurologic disorders (Table 1), the principal fea- neuron diseases (MND)* tures of which are attributable to dysfunction of upper and Primary MND lower motor neurons. Patients with amyotrophic lateral sclero- Idiopathic Sporadic amyotrophic lateral sclerosis sis (ALS), the most common motor neuron disease, manifest Western Pacific amyotrophic lateral variable combinations of both upper and lower motor neuron sclerosis-parkinsonism-dementia-complex signs, including spasticity, hyperreflexia, and extensive plantar Amyotrophic lateral sclerosis with frontal lobe dementia Monomelic MND signs (upper motor neuron signs); and progressive muscular Heritable weakness, fasciculations, and atrophy (lower motor neuron Autosomal dominant Familial amyotrophic lateral sclerosis signs), leading to fatal paralysis (1). Cognitive function is not Familial amyotrophic lateral sclerosis with dementia affected, and death usually occurs from complications attribut- Autosomal recessive able to difficulties in swallowing and respiration. Electromyo- Spinal muscular atrophy Neuroaxonal dystrophy graphy reveals fibrillations, and muscle biopsy reveals Pseudobulbar palsy denervation atrophy. However, there are no specific antemor- X-linked tem diagnostic tests. The histopathologic findings include den- Bulbospinal neuronopathy (Kennedy’s syndrome) ervation atrophy of skeletal muscle, and loss of motor neurons Secondary MND in the anterior horn of the spinal cord, motor nuclei, and the Infections motor cortex (2). At the light microscopic level, the motor neu- HIV, HTLV-1 Syphilis rons almost always contain axonal swellings or spheroids filled Poliomyelitis virus with misaligned neurofilament (NF) protein and accumula- Metabolic disease Hyperparathyroidism tions of NFs in the cell body (Figure 1) (2). Hexosaminidase deficiency Amyotrophic lateral sclerosis was first described in 1869 Autoimmune disease by the French physician Jean-Martin Charcot (3). The Greek Lymphoma Paraproteinemia derivation of the word amyotrophic means “muscles without Antigangliosides antibodies nourishment” (a means without, myo means muscle, and Neurotoxins trophic means nourishment). Lateral refers to the region of Aluminum, lead, mercury Lathyrus sativus toxin: BOAA the spinal cord where the axons of diseased and Cycad toxin: BMAA dysfunctioning motor neurons have degenerated and are re- HIV = human immunodeficiency virus; HTLV-1 = human T-cell placed by sclerosis, or scars. Also known as Lou Gehrig’s Dis- lymphotropic virus 1; BOAA = ␤-N-oxalyl-amino-L-alanine; BMAA = ␤- methyl-amino-alanine. *Adapted with permission from J. Lowe, G. Lennox, ease, ALS affects 4 to 6 individuals per 100,000 people and P. N. Leigh. 1997. Disorders of movement and system degenerations, p. 321. In D. I. Graham and P. L. Lantos (ed.), Greenfield’s Neuropathol- ogy, Sixth Edition. Oxford University Press, Inc., New York. Department of Comparative Medicine, Stanford University School of Medi- cine, Stanford, California *Address correspondence to: Dr. Ravi J. Tolwani, 287 Campus Drive, RAF worldwide (4). The disease usually affects individuals dur- 1, Quad 7, Building 330, Stanford, CA 94305-5410. ing the fifth decade of life, is progressive, and is uniformly fatal 480 Special Topic Overview Figure 1. (A) Perikaryl accumulation of neurofilaments in motor neuron disease. Silver impregnation; magnification x400. (B) Spheroids (arrowheads) in the anterior horn of an A ALS patient. One of the spheroids is compressing an adja- cent motor neuron (arrow). Silver impregnation; magnifica- tion x300. (With permission from: M. Iwata and A. Hirano, 1979. Current problems in the pathology of amyotrophic lat- eral sclerosis, p. 288–289. In H. M. Zimmerman [ed.], Progress in Neuropathology, Vol. 4. Raven Press, New York.) (5, 6). Most people die within 5 years after the onset of symptoms (5). Although ALS is familial in approximately 10% of patients, the cause of sporadic ALS (SALS), which accounts for the remaining 90% of all cases, is unknown (7, 8). The remarkable clinical similarity between familial ALS (FALS) and SALS, however, suggests that they share common pathways of motor neuron death. In 1993, Rosen et al. (9) discovered that 20% of pa- tients with FALS carried a mutation in the Cu/Zn su- peroxide dismutase 1 (Cu/Zn SOD1) gene, which is located on chromosome 21. This gene is a metalloen- zyme and is one of the principal oxygen-derived free radical scavengers and protectants against oxidant in- jury to the nervous system. This discovery strengthened the prominent hypothesis that dysfunction and subse- quent death of the motor neuron is related to anoma- B lous enzyme activity and cellular damage attributable to oxidant stress. However, this hypothesis recently has been challenged by Bruijn et al. (10), who propose that mutant SOD1 toxicity does not arise from superoxide- mediated oxidant stress but from some other as yet uni- dentified biochemical mechanism. This does not completely discount the role of oxidant stress in MND because many disease-related and normal biological processes, including normal aging, produce reactive oxygen species capable of damaging DNA proteins, car- bohydrates, and lipids (11). Nevertheless, why “at-risk” populations of motor neurons are selectively vulnerable to injury and the specific mechanisms that subse- quently lead to cytoskeletal dysfunction and cell death is not fully understood. Proposed pathways involving in MND are schematized in Figure 2. The catalogue of animal models for human MND is extensive (4, 12–19) and is generally divided into two categories: those that develop spontaneously, which are naturally acquired, inherited, or sporadic, and those that are Genetically Engineered Animal Models experimentally induced (Table 2). Here we summarize the of Motor Neuron Disease contributions and the limitations of selected experimentally To date, over 50 SOD1 mutations have been associated induced and spontaneously occurring animal models for with FALS (20), and the number will likely continue to grow. MND: murine transgenic motor neuron disease, and sponta- Genetically engineered mice with the most common muta- neously occurring murine, canine, and equine motor neuron tions—A4V, G93A, G37R or G86R (21–23)—have been the disease. Ideally, animal models should reflect the clinical most extensively studied and have contributed substantially to and neuropathologic features of the human disease as advancing our understanding of human MND. All these muta- closely as possible. Selected features of the aforementioned tions have induced MND in mice that is clinically and patho- animal models, including clinical characteristics and general logically similar to ALS. However, the gene copy number and pathologic features, are summarized and compared with level of gene expression significantly affects the pathologic those of ALS (Table 3). Extensive descriptions of the neuro- changes and age at onset in the various transgenic lines. Mice pathologic findings, particularly the variations in the animal expressing the G93A SOD1 mutation have been proposed to models at the light and electron microscopic levels, can be best reproduce ALS-like features (24, 25). found elsewhere (4, 11–18 and 4, 12–27, respectively) and The initial expectation was that these mutations cause are beyond the scope of this review. disease by lowering Cu/Zn SOD1 activity, as was observed 481 Vol 49, No 5 Laboratory Animal Science October 1999 Figure 2. Schematic model of proposed mechanisms leading to motor neuron disease (ER = endoplasmic reticulum, SOD = superoxide dismutase, Bcl-2 = a family of genes that regulates apoptosis). in the erythrocytes and tissues of ALS patients(26, 27). (10) may explain why the efficacy of antioxidant therapy in However, in several of the transgenic mouse lines (the G93A Cu/Zn SOD1 transgenic mice or in FALS patients is moder- and G37R mice in particular), Cu/Zn SOD1 activity was nor- ate at best. Treatment of the transgenic mice with two mal. In addition, Cu/Zn SOD1 knockout mice or mice glutaminergic inhibitors, riluzole and gabapentin,
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