Key Points
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There is evidence for the occurrence of programmed cell death (PCD) in several neurodegenerative disorders. Most of the evidence comes from studies in animal models of conditions such as Parkinson's and Huntington's diseases (PD and HD, respectively), and amyotrophic lateral sclerosis (ALS).
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There are two basic pathways of PCD: the mitochondrial (intrinsic) and the death receptor (extrinsic) pathways. Both pathways require the involvement of proteases known as caspases, the activity of which is regulated by different proteins of the so-called Bcl2 family.
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PCD has been proposed to take place in the brains of people with PD, although the best evidence in favour of this idea has come from studies of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of parkinsonism. Here, MPTP administration is accompanied by the activation of caspases. Moreover, drugs that interfere with early stages of PCD have been successful at preventing neurodegeneration in this model.
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PCD has also been documented to take place in association with ALS, mostly in transgenic models of the disease. In this case, interfering with PCD delays neuronal death and prolongs survival. However, as death eventually ensues, it seems that targeting PCD in ALS can slow the death process, but cannot stop it altogether.
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The data in relation to PCD in HD is still incomplete, but there are reasons to believe that caspase activation might participate in the neuronal death that accompanies this disease.
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The PCD machinery might be a good target for the development of drugs against these neurodegenerative disorders. However, PCD is only one of the processes that contributes to the pathological changes, making it necessary to think in terms of attacking the problem from other positions. In addition, therapeutic efforts should take into account that caspase activation might be a late process in the PCD cascade, a fact that might limit their usefulness as drug targets.
Abstract
Molecular pathways of programmed cell death (PCD) are activated in various neurodegenerative disorders including Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. In these diseases, PCD might be pathogenic, and targeting it might mitigate neurodegeneration. To identify potential neuroprotective targets within the PCD machinery, the expression and activity of some of its components have been altered by genetic or pharmacological means in experimental models of neurodegenerative diseases. The results of these studies have provided leads for the development of neuroprotective strategies for these progressive, disabling and often fatal disorders.
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Acknowledgements
We wish to acknowledge the support from the NIH/NINDS, the US Department of Defense, the Lowenstein Foundation, the Lillian Goldman Charitable Trust, the Parkinson's Disease Foundation, the American Parkinson's Disease Association, the Muscular Dystrophy Association, the ALS Association and Project-ALS. We also thank J.P. Vonsattel for his comments.
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Glossary
- TUNEL TECHNIQUE
-
This technique enables the visualization of cells undergoing apoptosis by labelling the broken ends of the double-stranded DNA with biotin-conjugated dUTP, using the enzyme terminal deoxynucleotidyl transferase.
- ZYMOGENS
-
The inactive precursors of enzymes — often transformed into the active enzyme by partial proteolysis.
- DOMINANT NEGATIVE
-
A mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.
- GAIN-OF-FUNCTION
-
A mutation that confers either a previously inexistent activity to the affected protein or increases a pre-existing funtion.
- PARAPTOSIS
-
A form of programmed cell death that is related to apoptosis. It is transcription dependent and features swelling of the endoplasmic reticulum and mitochondria. However, it does not depend on caspase activation, except for caspase 9, lacks internucleosomal DNA cleavage, and does not show other morphological hallmarks of apoptosis such as nuclear fragmentation.
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Vila, M., Przedborski, S. Targeting programmed cell death in neurodegenerative diseases. Nat Rev Neurosci 4, 365–375 (2003). https://doi.org/10.1038/nrn1100
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DOI: https://doi.org/10.1038/nrn1100
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