Motor neurone disease (amyotrophic lateral sclerosis)
Five thousand people in the UK have motor neurone disease (MND), known in the US as amyotrophic lateral sclerosis, ALS, and Lou Gehrig's disease (after a legendary baseball player of the 1930s). Two people get it every week in the UK, and most of them survive for only 2-5 years. It affects motor neurons (nerve cells), which control movement. There are several forms of the disease and although the causes are unknown, a number of ways in which motor neurons can be affected have been identified since 1992, and these have been studied in rats and mice
Approximately 10% of cases of MND are inherited and researchers have identified a dozen different genes that are associated with the disease
Strains of mice with a genetic form of the disease, either naturally occurring or genetically engineered, have improved our understanding of the disease and enable potential therapies to be tested. In 2002 scientists made transgenic rats with MND, which carry an abnormal human gene for an enzyme called superoxide dismutase (SOD1) . Faulty SOD1, caused by a number of different genetic mutations, is at the root of one-fifth of inherited MND cases.
The SOD1 mutation affects astrocytes, specialised non-neuronal brain cells, which then cause damage to previously healthy adjacent motor nerves . The mutant enzymes work by migrating to the powerhouses (mitochondria) of the spinal cord neurons and killing them from within . SOD1 mice are now a standard experimental model for MND and most treatments will be tested on these mice before progressing into clinical trials.
Scientists have also developed a model for motor neuron disease in zebrafish. These are particularly interesting because of their ability to regenerate neurons, unlike humans. In 2013, researchers discovered that neuron regeneration in zebrafish relies on the hormone dopamine
Genetic screening of zebrafish in 2012 led to the discovery of a gene, EPHA4, which influences the effects of MND . By stopping, or slowing down the activity of EPHA4, researchers led MND zebrafish and rodents to live longer. The researchers also discovered two human MND patients with mutations in their EPHA4 genes who had survived with MND for longer than expected . While this does not seem to reverse damage in mammals, it appears to slow the rate of decline making it a therapeutic target of interest.
In 2003, mutations in the gene encoding proteins known as dyneins were shown to produce MND-like symptoms in mice. Dyneins are responsible for transporting several different large objects around the cell and could help to explain the molecular basis for MND . Also, in 2003 it was found that a strain of MND mice called mnd2 had a mutation in a gene that codes for an enzyme called Omia , and this might provide a clue to some forms of the human disease.
One way that motor neurones can be damaged and destroyed became clear during the study of a new strain of mouse carrying a gene (NF-H) that causes nerve cells to produce too many filaments. Many MND patients carry a similar NF-H gene. The mice show characteristics of MND, and it is thought that the excess filaments cause MND by consuming excessive amounts of the nutrients required to keep nerve cells alive. These strains therefore make good models of this disease.
A gene for another growth factor, called VEGF, protects against MND in humans, and when it mutates, it results in an increased risk of developing the disease. VEGF protected mice with damaged motor nerves
In 2004, scientists bred a mouse with a form of MND called spinal and bulbar muscular atrophy ; the mice had abnormal androgen receptors, which interfered with VEGF, confirming the role of this growth factor in the disease. Shortly afterwards, it was shown that a single injection of a virus carrying a gene for VEGF delayed onset and slowed progression in MND mice. It also increased survival without any apparent adverse effects .
In 2013, human stem cells were injected into rats with MND to secrete VEGF and GDNF, another growth factor, which slowed the progression of the disease and prolonged lifespan . The cells only survived for 9 weeks and did not form new neurons, but were specifically used as a delivery system for these growth factors.
Inhibitors of an enzyme called caspase have prolonged the life of mice with NMD . There are 14 different caspases, and they play a key role in programmed cell death. While blocking all of them may have undesirable effects, blocking the function of one particular caspase improved the survival of MND mice from an average of 25 days to 35 days .Treatment with other enzymes called catalases has increased the survival of MND mice .
The drug known as Riluzole is current the only therapy available for MND. Although it is known to affect neurotransmission, its precise mechanism is still not entirely understood. Its neuroprotective effects were initially tested in rodents
About 20% of hereditary cases of MND are caused by a mutation that disrupts the heat shock response, a mechanism that protects cells from stress. A drug called arimoclomol improves muscle function in mice bearing this mutation and prolongs lifespan . This is now in phase II/III clinical trials, due to end December 2013, for MND patients with a SOD1 mutation .
Another drug, known as Ozanezumab, is currently in Phase II clinical trials. This targets Nogo-A, a protein that blocks nerve cell regeneration. Researchers previously found that mouse models and humans with MND have higher levels of Nogo-A in their muscles, and that levels of Nogo-A correlate with the severity of the condition .
Inflammation is notable issue in MND, as well as in Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. Research on SOD1 mouse models of MND has shown that immune system cells have an influence on the progression of the condition. A new drug, NP001, which alters the behaviour of macrophages to reduce inflammation in the brain has passed phase II clinical trials, which show that it is safe and well tolerated, and will be run through phase III trials in late 2013 .
Human umbilical stem cells, taken from the placental cord following birth, migrate to damaged areas of brain and spinal cord in MND mice. When human embryonic germ cells were injected into the fluid around the spinal cord of 15 paralysed rats the animals had improved control of their hind legs – but not in the way the scientists had expected. The implanted human cells produced two important molecules: one that improved nerve cell survival, and one that enabled nerve cells to remain in contact with each other. The rats’ own nerve cells were healthier in the animals that received human cells. Most of the implanted cells migrated into the spinal cord, becoming astrocytes and even motor neurons. However, only about four cells per animal became motor nerve cells that extended out from the spinal cord and reached into and controlled muscle .
- Brady, S (1995) Interfering with the runners Nature 375, 12
- Collard JF, Cote F and Julien JP (1995) Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis Nature 365, 61
- Subramaniam JR, Lyons WE, Liu J (2002) Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading. Nature Neuroscience 5, 301
- Clement AM, Nguyen MD, Roberts EA et al (2003) Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice Science 302, 113
- Liu J, Lillo C, Jonsson PA et al (2004) Toxicity of familial ALS-linked SOD1 mutants from selective Recruitment to spinal mitochondria Neuron 43, 5
- Reimer MM et al (2013) Dopamine from the Brain Promotes Spinal Motor Neuron Generation during Development and Adult Regeneration Developmental Cell doi:10.1016/j.devcel.2013.04.012
- Munro KM et al (2012) Differential Gene Expression in the EphA4 Knockout Spinal Cord and Analysis of the Inflammatory Response Following Spinal Cord Injury PLoS One 7(5):e37635 doi: 10.1371/journal.pone.0037635
- Annelies Van Hoecke et al (2012) EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans Nature Medicine 18, 1418–1422 doi:10.1038/nm.2901
- Hafezparest M, Klocke R, Ruhrberg C et al (2003) Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300, 808
- Jones JM, Datta P, Srinivasula SR et al (2003) Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice. Nature 425, 721
- Collard JF, Cote F, & Julien JP (1995) Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis. Nature 365, 61
- Lambrechts D, Storkebaum E, Morimoto M, et al (2003) VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nature Genetics 34, 383
- Oosthuyse B, Moons L, Storkebaum E et al (2001) Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nature Genetics, 28, 131
- Sopher BL, Thomas PS, LaFevre-Bernt MA (2004) Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration. Neuron 41(5), 687
- Azzouz M, Scott Ralph GS, Storkebaum E et al(2004). VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 428, 413
- Krakora D (2013) Synergistic Effects of GDNF and VEGF on Lifespan and Disease Progression in a Familial ALS Rat Model Molecular Therapy doi:10.1038/mt.2013.108
- Li M, Ona VO, Guégan C, Chen M et al(2000) functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science 288, 335
- Inoue H, Tsukita K, Iwasato T et al (2003) The crucial role of caspase-9 in the disease progression of a transgenic mouse model. EMBO J 22, 6665
- Poduslo JF, Whelan SL, Curran GL, Wengenack TM (2000) Therapeutic benefit of polyamine-modified catalase as a scavenger of hydrogen peroxide and nitric oxide in familial amyotrophic lateral sclerosis transgenics. Ann Neurol 48, 943
- Mizoule J et al (1985) 2-Amino-6-trifluoromethoxy benzothiazole, a possible antagonist of excitatory amino acid neurotransmission--I. Anticonvulsant properties Neuropharmacology 24(8):767-73
- Kieran D, Kalmar K, Dick JRT et al (2004) Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nature Medicine 10, 402
- Dupuis L et al (2002) Nogo provides a molecular marker for diagnosis of amyotrophic lateral sclerosis Neurobiology of Disease 10(3):358-365 DOI: 10.1006/nbdi.2002.0522
- Garbuzova-Davis S; Willing AE; Zigova T et al (2003) Intravenous administration of human umbilical cord blood cells in a mouse model of amyotrophic lateral sclerosis: distribution, migration, and differentiation J Hematotherapy Stem Cell Res 17, 255
- Kerr DA, Llado J, Shamblott MJ (2003) Human embryonic germ cell derivatives facilitate motor recovery of rats with diffuse motor neuron injury J Neurosci 23, 5131
Last edited: 5 November 2014 10:56