Regulation of caspases in the nervous system implications for functions in health and disease

Abstract

Caspases, initially identified as a family of proteases regulating cell death, have been found to have nonapoptotic functions as well. Some family members are critical for mediating programmed cell death in development. After development, caspases are downregulated in the nervous system, but continue to perform important nonapoptotic functions relevant for neurogenesis and synaptic plasticity. In neurodegenerative diseases, where aberrant neuronal death is an outstanding feature, there is an increase in caspase activity. The specific caspase death pathways leading to dysfunction and death have still not been fully clarified, despite the plethora of scientific literature addressing these issues. In this chapter, we will present the current knowledge of caspase activation and activity pathways, the current tools for examining caspases, and functions of caspases in the nervous system in health and in disease. Alzheimer's Disease, the most common neurodegenerative disorder, and cerebral ischemia, the most common cause of neurologic death, are used to illustrate our current understanding of death signaling in neurodegenerative diseases. A better understanding of how caspases function in health and disease would provide appropriate specific targets for the development of therapeutic interventions for these diseases. Life and death are exquisitely regulated at the cellular level from development through maturity. During development, neuronal death is the major factor shaping the nervous system. This death is mainly caspase-mediated apoptosis. Once the waves of developmental death have passed (death occurs at different times in different parts of the nervous system), there is downregulation of the death machinery, as the postmitotic neurons should live for the life of the organism. Aberrant neuronal death is a major part of neurodegenerative disorders, but there is still no clear understanding of the processes leading to the phenotypes of the various diseases. Even the type of death that occurs continues to be debated, whether it is apoptotic, necrotic, or autophagic, or some combination of these death mechanisms. Here, we will discuss the role that the caspases play in neuronal function, dysfunction, and death. First, we will discuss the regulation of caspase activation and activity. We will examine the current understanding of caspase function in developmental neuronal death and then illustrate the role of caspases in neuronal death in disease employing two diseases of neuronal loss, Alzheimer's Disease (AD), which is the most common chronic neurodegenerative disorder, and cerebral ischemia/stroke, the third most common cause of death in Western society, which is an acute neuronal disorder with chronic sequelae.

Fig. 1.. Mammalian caspases.

Mammalian caspases are schematically represented and grouped by activity. Yellow lines indicate cleavage sites.

Fig. 2.. Activation mechanisms of effector and initiator caspases.

Activation models for initiator and effector caspases are shown. Blue indicates inactive caspase while orange denotes activated caspase. Some of the activated caspases are subject to regulation by IAPs.

Fig. 3.. Caspase regulation: intrinsic pathway.

The intrinsic death pathway is activated by permeabilization of the mitochondria, leading to the release of cytochrome c and formation of the apoptosome, the caspase-9 activation platform. Once activated, caspase-9 can cleave and activate caspases-3 and -7. Caspases-3, -7, and -9 are subject to inhibition by XIAP. XIAP can be inhibited by Diablo/SMAC or HtrA2/Omi which are released from permeabilized mitochondria.

Fig. 4.. Caspase regulation: extrinsic pathway.

The extrinsic pathway is activated when a ligand binds to a death receptor; binding of FasL to the Fas receptor is shown. This leads to recruitment of an adaptor protein (FADD), which recruits caspase-8, forming the DISC, leading to dimerization and activation of caspase-8. Caspase-8 then cleaves and activates effector caspases. FLIP inhibits the formation of active caspase-8 dimers.

Fig. 5.. Proposed caspase actions in Alzheimer’s Disease.

The amyloid precursor protein (APP) can be proteolytically processed to release multiple products, including Aβ, C99, and C31. C99 and C31 are toxic to neurons. Aβ can form fibrils, which deposit as amyloid plaques and soluble oligomers and can lead to ER stress, caspase activation, tau hyperphosphorylation, neuronal dysfunction, and neuronal death.

Fig. 6.. Caspase activation in cerebral ischemia.

Caspases are activated in the ischemic core early in stroke and then in the penumbra as the stroke progresses.