Evidence for Apoptosis in Motor Neuron Disease ALS and Related Disorders

Motor neuron disease or amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) represents a neurodegenerative disorder in which apoptotic cell death has been invoked as a key pathogenetic mechanism. In ALS, progressive loss of upper and lower motor neurons results in extreme disability and ultimately death. As in AD and Parkinson's disease, both environmental and genetic factors have been suggested.131 Apoptotic cell death of motoneurons has been related to immunological attack and to failure of cell defenses against oxidative damage.132,133

The discovery of Cu,Zn-superoxide dismutase mutations as a cause for some cases of familial ALS has strongly supported a role for apoptosis since the effect of the mutation is to convert an antioxidant defense enzyme into a proapoptotic gene.134 Furthermore, other rare cases of familial ALS have been associated with NAIP mutations.135 This suggests that ALS may well be very similar to Parkinson's disease and late-onset AD in that a number of specific gene defects or allelic effects may be identified, accounting for 25 to 50% of familial cases. Environmental factors most likely interact with these genes to determine onset and character of illness. Many of the remaining cases may result from multiple genetic factors in combination with stronger and more adverse environmental or aging-related events. It is important to realize that the identified genes to date only account for a proportion of the familial ALS cases, and that most ALS cases (95%) are sporadic.

The importance of understanding the pathogenesis of ALS for other neu-rodegenerative disorders is that apoptotic cell death may be the major mode of motor neuron loss.136-139 The issue raised for excitoxic injury to the nervous system is the potential for both necrotic and apoptotic cell death with perhaps all intermediates depending on the timing and amount of injury.23,24 In ALS, there is considerable evidence for excitotoxicity as a mode of cell injury.140-144

Alterations in buffering of extracellular glutamate during cellular reactions to injury may result in neuronal cell injury and triggering of apoptosis.143,144 For example, alterations in glutamate transporters might result during aging or as a result of previous cellular injury. ALS and motor neuron disorders stand, therefore, as an example of apoptotic cell injury with modulation by both genetic and environmental events. In addition, some of these defects may arise from defective RNA splicing, as has been suggested for spinal muscular atrophy cases with mutations in the SMN gene. This gene may code for an RNA-splicing enzyme.145 Abnormal RNA splicing may be a common mechanism in age-related neurodegenerative diseases.

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