The kinder side of killer proteases: Caspase activation contributes to neuroprotection and CNS remodeling

Abstract

Caspases are a family of cysteine proteases that are expressed as inactive zymogens and undergo proteolytic maturation in a sequential manner in which initiator caspases cleave and activate the effector caspases 3, 6 and 7. Effector caspases cleave structural proteins, signaling molecules, DNA repair enzymes and proteins which inhibit apoptosis. Activation of effector, or executioner, caspases has historically been viewed as a terminal event in the process of programmed cell death. Emerging evidence now suggests a broader role for activated caspases in cellular maturation, differentiation and other non-lethal events. The importance of activated caspases in normal cell development and signaling has recently been extended to the CNS where these proteases have been shown to contribute to axon guidance, synaptic plasticity and neuroprotection. This review will focus on the adaptive roles activated caspases in maintaining viability, the mechanisms by which caspases are held in check so as not produce apoptotic cell death and the ramifications of these observations in the treatment of neurological disorders.

Caspase‐3 activation in astrocytes following postnatal excitotoxic damage correlates with cytoskeletal remodeling but not with cell death or proliferation

“…Other Non-Apoptotic Roles of Caspase-3 An important conclusion of this study is that cleaved caspase-3 is found in surviving reactive astrocytes, supporting the hypothesis of a non-apoptotic role of astroglial cleaved caspase-3, as has been postulated in other cell types, where non-apoptotic activities of caspases include the regulation of cell proliferation and differentiation (for review see McLaughlin, 2004;Schwerk and Schulze-Osthoff, 2003). One of the first described nonapoptotic roles of caspase-3 was the demonstration that caspase-3 cleavage is a physiological step during T lymphocyte activation and mitogenic induction (Miossec et al, 1997;Wilhelm et al, 1998).…”

“…Second, cleavage of FoxO transcription factors, like FoxO3a, that contain a conserved caspase-3 cleavage site (Charvet et al, 2003), could also play a role in the modulation of gene expression during glial differentiation or astrogliosis. Third, it has been suggested that caspase-3 could serve as a mechanism of protein degradation required for the cellular response to changes in extrinsic signals (McLaughlin, 2004).…”

“…Recent studies, however, provide substantial evidence for caspase function in non-apoptotic cellular events such as cell cycle regulation, migration, and differentiation in a variety of cell types (McLaughlin, 2004;Schwerk and Schulze-Osthoff, 2003). Although the preponderance of data has emerged from work in the immune system and peripheral organs, several studies have also suggested non-apoptotic roles of caspase-3 in the CNS.…”

Gadd45 Proteins Induce G2/M Arrest and Modulate Apoptosis in Kidney Cells Exposed to Hyperosmotic Stress

“…For instance, irreversible commitment to apoptosis in a B cell lymphoma cell line exposed to oxidative stress occurs between 48 and 72 h (54). In addition, escape of cells from apoptosis has been documented before, and emerging evidence demonstrates that caspase activation can also be indicative of other, nonlethal processes (55).…”

Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology

“…Although the hypothesis that apoptosis plays a role in AD neurodegeneration remains controversial, recent evidence suggests that caspase activation can occur independent of cell death and may be neuroprotective (67)(68)(69). In addition, caspase activation is implicated in long-term potentiation and neurite extension (70). However, caspase-cleaved tau leads to neurite retraction in vitro (71) and thus may contribute to synaptic deficits and cellular demise.…”