ReviewPathoetiology of motor neuron disease: new insights from genetics and animal models
Introduction
One of the most perplexing features of many acquired and hereditary nervous system disorders is the highly selective neuronal vulnerability evident pathologically that determines the unique clinical signature of the condition. This selective involvement occurs despite the fact that CNS neurons are highly specialised cells which have a broadly similar function, to transmit information through an ability to convert chemical messages into an informative action potential sequence, and a broadly similar physiology and metabolism. A prime example of selective neuronal vulnerability occurs in motor neuron disease (ALS) where at a clinical level, a highly selective degeneration of the motor system, both corticospinal and alpha motor neurons, leads to a devastating and ultimately fatal paralytic illness in adult life. There has been a view that achievement of a clear understanding of selective motor neuron loss in ALS would unlock the secrets of this condition.
Section snippets
What clinical clues are there to pathoetiology?
Motor neuron disease is a highly reproducible syndrome, in its archetypal form ALS, with onset of weakness, wasting and fasciculation indicating diseased anterior horn cells often in a single myotome then spread into adjacent spinal cord segments, and at some stage typically involvement of corticospinal motor neurons, with the evolution of a progressive paralytic disorder. Several clinical features run true to form.
The disorder begins in a very restricted manner. Clearly some anterior horn
Genetic clues
Up to 10% of cases of human ALS have an autosomal dominant inheritance with several large familial aggregations. In keeping with other neurodegenerative disorders of later life, candidate gene approaches to ALS have been undertaken in the belief that determination of affected genes in the rare familial forms may cast a gleam of understanding on the common sporadic variance. These hopes were advanced significantly with the identification of mutations of the copper, zinc, SOD1 gene in 20% of
Oxidative stress
The enzymatic function of SOD1 is to catalyse the conversion of potentially toxic superoxide anion to molecular oxygen and water, a step of which involves the dismutation of superoxide to hydrogen peroxide.6 The discovery of mutations in the gene for this enzyme as a cause of fALS lead initially to the suggestion that free radical scavenging in the cytosol was likely to be deficient.1 However most of the more than 50 recognised SOD1 mutations do not substantially effect dismutase function, and
Neurofilament alterations
Several lines of evidence suggest that neurofilament abnormalities may contribute to ALS. A key pathological feature in both fALS and sALS is the accumulation and abnormal assembly of neuro filaments in the soma and proximal axon. Motor neurons, both primary and secondary, are large cells with a higher neurofilament content than other neurons. NF proteins include three subunits, NF-H, NF-M and NF-L and an assembly of neurofilaments involves a polymerization of NF-L with either NF-M or NF-H. The
Excitotoxicity and calcium
Excitotoxicity, mediated by sustained activation of glutamate receptors is a major potential mechanism of neuronal death. The major glutamate transporter, EAAT2, is a high affinity transporter which rapidly moves released glutamate into astrocytes. A loss of this transporter has been demonstrated in sporadic ALS patients28 probably due to selective mRNA splicing errors,29 but unlikely to be a primary factor in the pathogenesis of ALS.30
SOD1 mice have increased levels of aspartate and glutamate
Protein aggregation
The discovery that insoluble β-amyloid aggregation is the central pathoetiological feature of Alzheimer dementia has led to a search for insoluble protein aggregation in other neurodegenerative disorders with intriguing results. Mutant SOD1 is believed to be a component of neuronal and astrocytic inclusion bodies in the anterior horn area of the spinal cord of patients with SOD1 mutated fALS and in SOD1 mice.37 Higher molecular forms of mutant SOD1 (believed to be aggregates) have been observed
Vascular endothelial growth factor (VEGF)
A new player in the last year is VEGF, a cytokine crucial in small vessel angiogenesis. Mice carrying a targeted deletion of the hypoxia response element in the VEGF promoter were produced in a cancer medicine programme as a possible modulator of tumour growth and to the investigators surprise lead to a characteristic motor neuron disease phenotype.4 The mechanism of this is not clear and in particular whether it relates to a vascular process or a yet to be discovered neurotrophic role of VEGF
Mitochondrial toxicity
Mitochondrial vacuolation has been found to be the first pathological marker of motor neuron damage in G93A SOD1 mice, immediately preceding the onset of paralysis.39
A recent surprise came from the discovery that a significant fraction of wild-type SOD1 appears to be localised to the mitochondrial intermembrane space,40 raising the possibility of a direct toxic interaction of mutant SOD1 with mitochondria. The recent explosion of research into programmed cell death has placed the mitochondrion
Synthesis
A great deal is now known about motor neuron function in health and disease but a single clear explanation for selective motor neuron vulnerability has not emerged. SOD1 mutations through either toxic gain of function or protein aggregation or both can lead to neuronal loss. Motor neurons are large cells with high metabolic demands and may be particularly vulnerable to free radical mediated injury. Glutamate related excitotoxicity contributes to motor neuron loss and in SOD1 positive ALS, this
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