Programmed cell death in amyotrophic lateral sclerosis: a mechanism of pathogenic and therapeutic importance

Background: Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disease of adulthood. Mounting evidence indicates that molecular components of the programmed cell death (PCD) machinery are implicated in the demise of motor neurons in this illness. PCD, rather than being passive, is an active mechanism of cell death tightly regulated by multiple molecular pathways. Review Summary: Thus far, little is known about the etiology and the pathogenesis of ALS. However, several studies support the view that PCD is instrumental in ALS neurodegenerative process. Data from postmortem ALS specimens and from experimental models of ALS show that some dying motor neurons exhibit features reminiscent of apoptosis, a prominent morphologic form of PCD. In addition, many key molecular components of the PCD machinery are activated in ALS spinal cords. Supporting the significance of these alterations, genetic and pharmacological interventions aimed at mitigating these changes prolong survival and attenuate neurodegeneration in a mouse model of ALS. Conclusion: The morphologic evidence of PCD in ALS remains an equivocal. However, the molecular evidence of PCD involvement in ALS is compelling. Moreover, preclinical studies in mice demonstrate the beneficial effects of targeting PCD on ALS-like neurodegeneration. The neurologist needs to be familiar with the concept of PCD and the potential significance of targeting PCD as neuroprotective strategies for ALS.