Caspase-Dependent and -Independent Neuronal Death: Two Distinct Pathways to Neuronal Injury

Caspases are cysteine proteases that mediate apoptotic death in a variety of cellular systems, including neurons. Caspases are activated through extrinsic or intrinsic pathways. The latter is used by most neurons in most situations. In this pathway, release of mitochondrial cytochrome c into the cytoplasm induces formation of the apoptosome, which leads to the activation of caspase 9 and subsequently other caspases. Recent data demonstrate that when caspase activation is inhibited at or downstream of the apoptosome, neurons undergo a delayed, caspase-independent death. Furthermore, there are instances, most notably following excitotoxic injury and calcium overload, in which the direct cell death pathway elicited differs from classical apoptosis. The molecular and biochemical features of such caspase-independent, nonapoptotic forms of neuronal death are just beginning to be elucidated, but alterations at the level of the mitochondria and noncaspase proteases play significant roles. Mitochondrial alterations in caspase-independent death may include energy depletion, generation of free radicals, opening of the permeability transition pore, and release of cytotoxic proteins, such as apoptosis-inducing factor. The particular mechanisms employed can be context dependent. In disease states, in which a combination of apoptotic and nonapoptotic death occurs, therapeutic strategies need to take into account both caspase-dependent and -independent pathways.