The pathology of motor neuron diseases (MNDs) such as amyotrophic lateral sclerosis (ALS) involves neuronal apoptosis. However, elucidating whether apoptosis is causal or a consequence of disease pathology is crucial for determining whether apoptotic pathways can be targeted therapeutically. To investigate this issue, Reyes et al. crossed a genetic mouse model of ALS (SodG93A) with mice that conditionally lack two key proapoptotic proteins – BAX and BAK, which initiate mitochondrial apoptosis – in the CNS. In contrast to SodG93A mice, the resultant SodG93ADKOCNS mice maintained motor neuron function and viability, owing to genetic disruption of mitocondrial apoptosis in the CNS. In addition, neuronal Bax and Bak deletion prevented axonal degradation and the onset of ALS symptoms, as well as weight loss, paralysis and reduced survival. This study demonstrates that mitochondrial apoptosis plays a direct role in ALS pathogenesis and suggests that inhibiting this pathway might be an effective strategy for treating ALS and other MNDs.

Reyes NA, Fisher JK, Austgen K, VandenBerg S, Huang EJ, Oakes SA (2010). Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis. J Clin Invest. 120, 3673– 3679.
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2010