Caspase 3

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Introduction

Many studies have proved the role of caspases in programmed cell death. In mammals, two main pathways for activating the caspase cascade have evolved, namely the mitochondrial pathway and the death receptor pathway, which are also called the intrinsic pathway and the extrinsic pathway, respectively. In the intrinsic pathway, one of the main events is mitochondrial outer membrane permeabilization (MOMP). The result of MOMP is the release of cytochrome c into the cytoplasm in the presence of dATP, which induces the formation of apoptosome complex. In turn, this complex binds and activates procaspase-9. Mature caspase-9 remains bound to the apoptosome, recruiting and activating executioner caspase-3 and/or caspase-7. The extrinsic pathway involves signal transduction from a cell surface receptor. Similar to the death domain (DD), Fas-associated DD protein (FADD) contains a death effector domain (DED) and recruits the DED-containing procaspase-8 into the death receptor-induced signaling complex (DISC). Procaspase-8 is activated into caspase-8 with enzymatic activity, which in turn activates the downstream effector caspases. Both the extrinsic and intrinsic pathways converge at caspase-3. Caspase-3, together with other effector caspases (such as caspase-7 and caspase-6), coordinate the breakdown of many cell structures by cleaving specific substrates. These caspase-mediated cleavages produce the phenotypic changes observed in the apoptotic cells.

Figure 1. Intrinsic and extrinsic pathways of caspase activation in mammals (D'Amelio, M.; Cavallucci, V.; Cecconi, F. 2010)

Caspase-3 in Neurodevelopment and Differentiation

A large number of studies have proved the close connection between caspases and neurophysiology. Caspase-3 not only plays an important role in cell apoptosis but also in the physiological process that does not cause cell death. Cell death in the developing nervous system is a phenomenon that has been recognized as early as one hundred years ago. It is estimated that apoptosis can eliminate half of the original cell population produced during the development of the nervous system, thereby optimizing synaptic connections and removing unnecessary neurons. In the developing nervous system, apoptosis is observed in the early stages of neural tube formation and persists during the terminal differentiation of neural networks involving neurons, glial and neural progenitor cells. With a few notable exceptions, neurons seem to mainly use the intrinsic pathway of apoptosis for cell death, and the abnormal brain development of knockout mice with altered caspase-3 activation highlights the core role of caspase-3 in neurodevelopment. Caspase-3 activation is generally considered to be one of the last steps of cell death. Although caspase-3 is a key protein in the execution of apoptosis, evidence also suggests that this enzyme may have some non-apoptotic roles. In the study of Fernando et al., the non-apoptotic effect of caspase-3 is not only related to cell death, but also closely related to the differentiation of neural stem cells. Their study shows that caspase-3 activity in neuronal progenitors promotes neurogenesis, especially when using an in vitro system (primary derived neuronal stem cells).

Figure 2. Nonapoptotic caspase-3 functions in neuronal cells (D'Amelio, M.; Cavallucci, V.; Cecconi, F. 2010)

Caspase-3 in Neurological Disease

Acute and chronic neurodegenerative diseases, including stroke, brain trauma, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and Parkinson’s disease (PD), are diseases characterized by extensive neuronal cell death. However, increasing clinical and morphological evidence suggests that the synapse loss that occurs in these diseases may occur before or independently of cell death. Three experimental models of ischemic injury have been described: (1) the middle cerebral artery occlusion (MCAo) model of ischemia in adult mice and rats; (2) the carotid artery occlusion model of ischemia in adult rats and gerbils; (3) the model of hypoxic–ischemic brain injury in neonatal rats. Caspase-3 was activated in all three ischemic injury models. Compared with acute neuronal trauma, chronic neurodegenerative diseases are also characterized by the loss of selective neuronal populations, which often leads to loss of cognitive and motor functions. Many studies have studied the role of caspases, especially caspase-3, in neurodegenerative diseases. Several proteins related to neurodegenerative diseases (such as huntingtin, amyloid precursor protein and presenilin) are also cleaved by caspase-3. Based on these evidence, some researchers have put forward a challenging hypothesis that caspase-3-mediated cleavage of these proteins may promote the onset of neurodegenerative diseases and ultimately perform the final step of apoptosis.