Expert Reviews in Molecular Medicine: http://www.expertreviews.org/
DOI: 10.1017/S1462399406010854; 24 May 2006
Emily F. Goodall and Karen E. Morrison (2006) Amyotrophic lateral sclerosis (motor neuron disease): proposed mechanisms and pathways to treatment.
Expert Rev. Mol. Med. Vol. 8, Issue 11, DOI: 10.1017/S1462399406010854

Amyotrophic lateral sclerosis (motor neuron disease): proposed mechanisms and pathways to treatment

Emily F. Goodall and Karen E. Morrison

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by loss of motor neurons. The cause of disease is unknown other than in the rare cases of familial disease arising from mutations in the superoxide dismutase 1 gene. Many theories for pathogenesis have been proposed – including oxidative stress, excitotoxicity, mitochondrial dysfunction and abnormal protein aggregation – based on studies of human post mortem tissue, research on animal models, and in vitro work. Here we review the evidence for the main pathogenic mechanisms and outline how they might interact to cause motor neuron death. Clinical trials have as yet failed to identify any truly effective therapies in ALS, with only riluzole providing a modest improvement in survival. Ongoing trials are exploring the value of antiglutamatergic agents, including the cephalosporin antibiotic ceftriaxone, as well as antioxidants, mitochondrial enhancers and anti-apoptotic drugs. It is likely that effective therapy will involve combinations of agents acting on different mechanisms. Gene therapy with neurotrophic factors will soon be in clinical trials, while work on stem cell therapy remains preclinical. In addition to finding effective therapies, research also needs to identify early disease markers because therapy is likely to be of most benefit when given early in the course of disease.

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Figure 1. Outline of the human motor system.
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Figure 2. Ubiquitinated inclusions in a motor neuron cell body from a patient with amyotrophic lateral sclerosis.
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Figure 3. Overview diagram summarising some of the theories of amyotrophic lateral sclerosis pathogenesis.
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Figure 4. Glutamatergic transmission in the central nervous system.
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Figure 5. Model to show how some of the proposed mechanisms in amyotrophic lateral sclerosis could interact to cause motor neuron degeneration.
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Table 1. Pathological features seen in amyotrophic lateral sclerosis.
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Table 2. Genetic factors in amyotrophic lateral sclerosis.
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