Non-Canonical Roles of Apoptotic Caspases in the Nervous System (original) (raw)

Neuronal caspase-3 signaling: not only cell death

Cell Death & Differentiation, 2009

Caspases are a family of cysteinyl aspartate-specific proteases that are highly conserved in multicellular organisms and function as central regulators of apoptosis. A member of this family, caspase-3, has been identified as a key mediator of apoptosis in neuronal cells. Recent studies in snail, fly and rat suggest that caspase-3 also functions as a regulatory molecule in neurogenesis and synaptic activity. In this study, in addition to providing an overview of the mechanism of caspase-3 activation, we review genetic and pharmacological studies of apoptotic and nonapoptotic functions of caspase-3 and discuss the regulatory mechanism of caspase-3 for executing nonapoptotic functions in the central nervous system. Knowledge of biochemical pathway(s) for nonapoptotic activation and modulation of caspase-3 has potential implications for the understanding of synaptic failure in the pathophysiology of neurological disorders. Fine-tuning of caspase-3 lays down a new challenge in identifying pharmacological avenues for treatment of many neurological disorders.

Caspase-dependent apoptotic pathways in CNS injury

Molecular Neurobiology, 2001

Recent studies have suggested a role for neuronal apoptosis in cell loss following acute CNS injury as well as in chronic neurodegeneration. Caspases are a family of cysteine requiring aspartate proteases with sequence similarity to Ced-3 protein of Caenorhabditis elegans. These proteases have been found to contribute significantly to the morphological and biochemical manifestations of apoptotic cell death. Caspases are translated as inactive zymogens and become active after specific cleavage. Of the 14 identified caspases, caspase-3 appears to be the major effector of neuronal apoptosis induced by a variety of stimuli. A role for caspase-3 in injury-induced neuronal cell death has been established using semispecific peptide caspase inhibitors. This article reviews the current literature relating to pathways regulating caspase activation in apoptosis associated with acute and chronic neurodegeneration, and suggests that identification of critical upstream caspase regulatory mechanisms may permit more effective treatment of such disorders.

Brainiac Caspases: Beyond the Wall of Apoptosis

Frontiers in Cellular Neuroscience, 2019

For the last two decades, caspases, a family of cysteine-aspartic proteases, have evolved from being considered solely as regulators of apoptosis or inflammation to having a wider range of functions. In this mini review, we focus on the most recent "non-apoptotic" roles of caspases in the CNS, particularly in neurons, astrocytes and oligodendrocytes. Non-apoptotic caspase functions in microglia have already been reviewed extensively elsewhere. Here we discuss the involvement of caspases in the activation of the inflammasome, autophagy, and non-apoptotic forms of cell death such as necroptosis and pyroptosis. Also, we review the involvement of caspases in synapses and the processing of aggregates key to neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's diseases. Likewise, we mention the recently described involvement of caspases in mitochondrial biogenesis, which is a function independent of the enzymatic activity. We conclude discussing the relevance that "new" functions of caspases have in the CNS and the future of this field of research.

Caspase Function in Neuronal Death: Delineation of the Role of Caspases in Ischemia

Current Drug Target -CNS & Neurological Disorders, 2005

Cerebral ischemia is one of the major causes of morbidity and mortality in the Western world. Despite extensive research, adequate therapies are still elusive. Neuronal degeneration and death are hallmarks of stroke/ischemia. Understanding how the death machinery executes neuronal death in ischemia will provide therapeutic targets. Key to the death machinery are caspases: the family of cell death proteases. While much data has been published regarding caspase involvement in models of ischemia, the pathways have not been thoroughly defined. The specification of the caspases critical for death has been hampered by the use of nonspecific reagents. Thus many conclusions about specificity are unwarranted. In this review we discuss how caspases can be measured and review the existing knowledge of the roles of specific caspases in ischemia. We also discuss approaches to determining the molecules that execute ischemic death.

Apoptosis in caspase-inhibited neurons

Molecular medicine (Cambridge, Mass.), 2001

There is growing evidence of apoptosis in neurodegenerative disease. However, it is still unclear whether the pathological manifestations observed in slow neurodegenerative diseases are due to neuronal loss or whether they are related to independent degenerative events in the axodendritic network. It also remains elusive whether a single, caspase-based executing system involving caspases is responsible for neuronal loss by apoptosis. Long-term exposure to the microtubule-disassembling agent, colchicine, was used to disrupt the axodendritic network and eventually trigger caspase-3-mediated apoptosis in cultures of cerebellar granule cells. For this model, we investigated the role of Bcl-2 and caspases in neurite degeneration and death of neuronal somata. Early degeneration of the axodendritic network occurred by a Bcl-2 and caspase-independent mechanism. Conversely, apoptosis of the cell body was delayed by Bcl-2 and initially blocked by caspase inhibition. However, when caspase acti...

New Views on the Misconstrued: Executioner Caspases and Their Diverse Non-apoptotic Roles

Neuron, 2015

Initially characterized for their roles in apoptosis, executioner caspases have emerged as important regulators of an array of cellular activities. This is especially true in the nervous system, where sublethal caspase activity has been implicated in axonal pathfinding and branching, axonal degeneration, dendrite pruning, regeneration, long-term depression, and metaplasticity. Here we examine the roles of sublethal executioner caspase activity in nervous system development and maintenance, consider the mechanisms that locally activate and restrain these potential killers, and discuss how their activity be subverted in neurodegenerative disease.

Maier, J. K. et al. The neuronal apoptosis inhibitory protein is a direct inhibitor of caspases 3 and 7. J. Neurosci. 22, 2035-2043

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

The neuronal apoptosis inhibitory protein (NAIP) was identified as a candidate gene for the inherited neurodegenerative disorder spinal muscular atrophy. NAIP is the founding member of a human protein family that is characterized by highly conserved N-terminal motifs called baculovirus inhibitor of apoptosis repeats (BIR). Five members of the human family of inhibitor of apoptosis proteins including NAIP have been shown to be antiapoptotic in various systems. To date, a mechanism for the antiapoptotic effect of NAIP has not been elucidated. To investigate NAIP function, we found cytoprotection of NAIP-expressing primary cortical neurons treated to undergo caspase-3-dependent apoptosis. The additional treatment of these neurons with the pancaspase inhibitor boc-aspartyl(OMe)-fluoromethylketone did not result in increased survival. Similar cytoprotective effects were obtained using HeLa cells transiently transfected with a NAIP N-terminal construct and treated to undergo a caspase-3-d...

Caspase Family Proteases and Apoptosis

Acta Biochimica Et Biophysica Sinica, 2005

Apoptosis, or programmed cell death, is an essential physiological process that plays a critical role in development and tissue homeostasis. The progress of apoptosis is regulated in an orderly way by a series of signal cascades under certain circumstances. The caspase-cascade system plays vital roles in the induction, transduction and amplification of intracellular apoptotic signals. Caspases, closely associated with apoptosis, are aspartate-specific cysteine proteases and members of the interleukin-1β-converting enzyme family. The activation and function of caspases, involved in the delicate caspase-cascade system, are regulated by various kinds of molecules, such as the inhibitor of apoptosis protein, Bcl-2 family proteins, calpain, and Ca 2+ . Based on the latest research, the members of the caspase family, caspase-cascade system and caspase-regulating molecules involved in apoptosis are reviewed.

Role of Caspases in N-Methyl-d-Aspartate-Induced Apoptosis in Cerebrocortical Neurons

Journal of Neurochemistry, 2002

Overactivation of glutamate receptors mediates neuronal death in several acute and chronic neurodegenerative diseases. The intracellular processes underlying this form of death, however, remain poorly understood. Depending on the severity of insult, Nmethyl-o-aspartate (NMDA) receptor activation induces either apoptosis or necrosis. Cysteine proteases related to interleukin-1/3-converting enzyme (ICE), recently termed caspases, appear necessary for neuronal apoptosis in vivo and in vitro. To determine whether caspases play a role in NMDA-induced apoptosis, we used two functionally distinct approaches to decrease substrate cleavage by caspases. One is a novel peptide (V-lCE~h)that contains the caspase catalytic site and acts as a pseudoenzyme that binds caspase substrates and prevents their cleavage. The other is a pseudosubstrate peptide (Z-VAD . fmk) that inhibits caspase activity. Pretreatment with either V-ICESh or Z-VAD fmk protects cerebrocortical neurons from NMDA-induced apoptosis, suggesting a role for caspases in NMDA-induced apoptosis. To explore the signaling pathways involved, we looked at the effects of NMDA receptor activation on Ca 2 influx, production of reactive oxygen species (ROS), mitochondrial membrane potential, and lipid peroxidation. Neither NMDA-induced Ca2ĩnflux nor the initial collapse of mitochondrial membrane potential could be prevented by pretreatment with V-lCE~5 or Z-VAD fmk. In contrast, ROS formation and lipid peroxidation were completely blocked by both V-lCEI~hand Z-VAD fmk. Taken together, our results suggest that Ca 2ĩ nflux and mitochondrial depolarization occur upstream from caspase activation, whereas ROS formation and lipid peroxidation may be downstream events in the cascade leading to cortical neuronal apoptosis.