Programmed Cell Death Mechanisms in Neurological Disease

Abstract

Programmed cell death (pcd) is a form of cell death in which the cell plays an active role in its own demise. Pcd plays a critical role in the development of the nervous system, as well as in its response to insult. Both anti-pcd and pro-pcd modulators play prominent roles in development and disease, including neurodegeneration, cancer, and ischemic vascular disease, among others. Over 100,000 published studies on one form of programmed cell death-apoptosis-have appeared, but recent studies from multiple laboratories suggest the existence of non-apoptotic forms of programmed cell death, such as autophagic programmed cell death. In addition, there appear to be programmatic cell deaths that do not fit the criteria for either apoptosis or autophagic cell death, arguing that additional programs may also be available to cells. Constructing a mechanistic taxonomy of all forms of pcd-based on inhibitors, activators, and identified biochemical pathways involved in each form of pcd-should offer new insight into cell deaths associated with various disease states, and ultimately offer new therapeutic approaches.

Human Caspases: Activation, Specificity, and Regulation

“…Additional criteria include prodomain length and substrate preference (4) and phylogenetic relationships (11). For several years, caspases were simply divided into "apoptotic" and "pro-inflammatory," and this classification remains useful to some extent, although most apoptotic candidates (caspase-2, -3, -6, -7, -8, -9, and -10) have had at least one non-apoptotic role attributed to them (12). Similarly, typical "non-apoptotic" members such as caspase-1, -4, and -5 are proposed to induce "pyroptosis," a form of death associated with massive activation of inflammatory cells (13).…”

Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis

“…Neuronal tissues are susceptible to a number of insults that contribute to motor neuron dysfunction and cell death, including misfolded proteins, reactive oxygen and nitrogen species, calcium entry, excitotoxicity, trophic factor withdrawal, death receptor activation, and mitochondrial complex inhibition (1,2). There is abundant evidence that injured motor neurons undergo apoptosis in a variety of motor neuron diseases (MNDs).…”

Neurodegenerative diseases: failures in brain connectivity?

“…Both apoptosis and autophagy, as well as cell death processes that do not have all the classic features of either, have been implicated in neurodegeneration. 8 In apoptosis, in particular, cells exist in a state of equilibrium between the pro-and anti-apoptotic proteins that constitute the programme, and death occurs when this equilibrium is disturbed. In addition, cells express natural cytoprotective factors, the activity of which must also be overcome for death to occur.…”