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Programmed cell death in amyotrophic lateral sclerosis: a mechanism of pathogenic and therapeutic importance
1Department of Neurology, Center of Neurobiology and Behavior, Columbia University, New York, NY, USA. SP30@columbia.edu
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.
Conclusions:
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.
Insights
Programmed cell death (PCD) pathways are molecularly activated in amyotrophic lateral sclerosis (ALS). Targeting PCD shows promise for neuroprotection in ALS mouse models, suggesting therapeutic potential.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset paralytic disease.
- Motor neuron degeneration in ALS is increasingly linked to programmed cell death (PCD) pathways.
- PCD is an active, regulated cellular process, not merely passive cell death.
Purpose of the Study:
- To review the evidence for programmed cell death (PCD) involvement in amyotrophic lateral sclerosis (ALS) pathogenesis.
- To evaluate the potential of targeting PCD as a neuroprotective strategy for ALS.
Main Methods:
- Analysis of postmortem ALS spinal cord specimens.
- Examination of experimental ALS mouse models.
- Review of genetic and pharmacological intervention studies.
Main Results:
- While morphologic evidence of PCD in ALS motor neurons is equivocal, molecular evidence is compelling.
- Key PCD pathway components are activated in ALS spinal cords.
- Interventions targeting PCD pathways prolonged survival and reduced neurodegeneration in an ALS mouse model.
Conclusions:
- Molecular evidence strongly implicates PCD in ALS neurodegeneration.
- Preclinical studies demonstrate that targeting PCD offers neuroprotective benefits in ALS models.
- Neurologists should consider PCD mechanisms and their therapeutic targeting for ALS neuroprotection.
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