Oxidative stress and motor neurone disease

The effects of oxidative stress within post mitotic cells such as neurones may be cumulative, and injury by free radical species is a major potential cause of the age-related deterioration in neuronal function seen in several neurodegenerative diseases, There is strong evidence that oxidative stress plays an important role in the pathogenesis of motor neurone disease (MND) , Point mutations in the antioxidant enzyme Cu,Zn superoxide dismutase (SOD 1) are found in some pedigrees with the familiar form of MND, How mutations in this ubiquitous enzyme cause the relatively selective cell death of spe cific groups of motor neurones is not clear, although a number of hypothese s have been forwarded. These include (1) the formation of hydroxyl radicals , (2) the catalysis of reactions of the nitrogen centred oxidant species pe roxynitrite, (3) toxicity of copper or zinc and (4) protein aggregation, So me experimental support for these different hypotheses has been produced by manipulating cells in culture to express the mutant SOD1 proteins and by g enerating transgenic mice which over-express mutant SOD1, Observations in t hese model systems are, in some cases at least, supported by observations m ade on pathological material from patients with similar SOD1 mutations, Fur thermore, there are reports of evidence of free radical mediated damage to neurones in the sporadic form of MND. Several lines of evidence suggest tha t alterations in the glutamatergic neurotransmitter system may also play a key role in the injury to motor neurones in sporadic MND, There are several important subcellular targets, which may be preferentially impaired within motor neurones, including neurofilament proteins and mitochondria. Future research will need to identify the aspects of the molecular and physiologic al phenotype of human motor neurones that makes them susceptible to degener ation in MND, and to identify those genetic and environmental factors which combine to cause this disease in individuals and in familiar pedigrees.