This intriguing paper uses a well-executed genetic approach to demonstrate the significance of the calcium-dependent cysteine protease calpains and the cathepsin-like aspartyl proteases in neurodegeneration. It has been postulated that, in mammalian systems, calpains and lysosomal enzymes such as cathepsins play a role in acute (such as ischemic brain damage) and chronic (such as Alzheimer's disease) neurodegeneration. However, due to the complexity of the mammalian nervous system and the lack of suitable pharmacologic inhibitors, it has been difficult to unambiguously demonstrate the importance of these enzymes in neurodegeneration. This study not only shows that these enzymes play an essential role in neuronal death, but also offers a cascade of events initiating from Ca influx to activation of calpains and the aspartyl proteases.

This study also suggests that caspases are responsible for apoptosis during development, whereas calpains and the aspartyl proteases are more responsible for neurodegeneration in C. elegans. The picture may not be as black and white in...  Read more

This intriguing paper uses a well-executed genetic approach to demonstrate the significance of the calcium-dependent cysteine protease calpains and the cathepsin-like aspartyl proteases in neurodegeneration. It has been postulated that, in mammalian systems, calpains and lysosomal enzymes such as cathepsins play a role in acute (such as ischemic brain damage) and chronic (such as Alzheimer's disease) neurodegeneration. However, due to the complexity of the mammalian nervous system and the lack of suitable pharmacologic inhibitors, it has been difficult to unambiguously demonstrate the importance of these enzymes in neurodegeneration. This study not only shows that these enzymes play an essential role in neuronal death, but also offers a cascade of events initiating from Ca influx to activation of calpains and the aspartyl proteases.

This study also suggests that caspases are responsible for apoptosis during development, whereas calpains and the aspartyl proteases are more responsible for neurodegeneration in C. elegans. The picture may not be as black and white in mammals. There is a large body of literature describing the involvement of caspases in a number of neurodegenerative diseases. This underscores the challenge we are facing in combating neurodegenerative diseases such as Alzheimer's in that we need to deal with multiple pathways to save neurons from dying.

View all comments by Li-Huei Tsai

In their careful genetic analysis in C. elegans, Syntichaki and colleagues present a compelling case that calpains and aspartyl proteases are essential participants in a form of neurodegeneration that occurs independently of CED-3 and several related proteases important to programmed cell death in the nematode. The study provides the most direct evidence to date that activation of these two proteolytic systems can execute death of mature neurons in situ, and offers a valuable window into the still-murky realm of "necrotic" cell death.

Although the genetic perturbations were not intended to model a specific human disease, the cellular pathways involved and the outcomes invite interesting comparisons to findings in Alzheimer’s disease. In AD, calpain activation and high expression of certain lysosomal proteases, including the aspartyl protease cathepsin D, develop very early in neurons in vulnerable areas and become robust as the neurons begin to show other signs of metabolic compromise. Growing evidence links the actions of these two proteolytic systems in the...  Read more

In their careful genetic analysis in C. elegans, Syntichaki and colleagues present a compelling case that calpains and aspartyl proteases are essential participants in a form of neurodegeneration that occurs independently of CED-3 and several related proteases important to programmed cell death in the nematode. The study provides the most direct evidence to date that activation of these two proteolytic systems can execute death of mature neurons in situ, and offers a valuable window into the still-murky realm of "necrotic" cell death.

Although the genetic perturbations were not intended to model a specific human disease, the cellular pathways involved and the outcomes invite interesting comparisons to findings in Alzheimer’s disease. In AD, calpain activation and high expression of certain lysosomal proteases, including the aspartyl protease cathepsin D, develop very early in neurons in vulnerable areas and become robust as the neurons begin to show other signs of metabolic compromise. Growing evidence links the actions of these two proteolytic systems in the Alzheimer brain to cytoskeletal and APP-related pathobiology as well as to neurodegeneration (reviewed in Ann.NY.Acad.Sci, 2000). In the C. elegans model, neurodegeneration was elicited by inducing the release of calcium from endoplasmic reticulum stores. By somewhat different mechanisms, mutant forms of presenilin that cause familial AD potentiate agonist-induced release of calcium from the ER of neurons in transgenic mice. Although neuronal death has not been seen in these mice, the sensitivity to excitotoxin-induced neurodegeneration is increased. Other factors important to AD development—aging, oxidative stress, and Aβ toxicity—also promote calcium dysregulation as well as activate calpain and cathepsin D. The nematode findings should stimulate research on how these proteolytic pathways are regulated in the brain and behave in mammalian models of human neurodegenerative disease.

The Syntichaki et al. results also touch on an emerging theme within cell death circles that the different protease systems of the cell interact extensively. This cross-talk has contributed to the present confusing picture in aging-related neurodegenerative disease of which protease systems mediate neuronal cell death. Given the extent of these interactions, it would not be surprising if some caspase activation could also be detected late in the demise of neurons in the worm model, even though its role is minor. Until more specific protease inhibitors are developed, the genetic approach taken by Syntichaki et al. holds the greatest promise for sorting out which activated proteases in a dying cell are essential to the particular degenerative process and are, perhaps, viable therapeutic targets. The prospect that multiple protease systems contribute to neurodegeneration does pose a challenge for therapy development. At the same time, the substantial rescue seen in this study even when only one of the implicated proteases was blocked provides a ray of hope that targeting the pathological activation of "utility" proteases, a situation often considered too catastrophic or end-stage to rescue, may yet have a place in the treatment of AD and related disorders.

View all comments by Ralph Nixon