Gaining notoriety through translocation: a case of the apoptosis-inducing factor (AIF) in poly (ADP-ribose) polymerase (PARP)-1-dependent neuronal death

Abstract

The enormous global burden of neurological and neurodegenerative diseases compels a frantic search for novel neurotherapeutics that will address the underlying pathologies, unlike most of the current pharmacological interventions that predominantly merely relieve symptoms of disease. A major challenge, however, is that the central nervous system (CNS), in contrast to most other well-studied systems, exhibits significant complexity that perhaps makes it one of the, if not the, least tractable to date, at least on the drug discovery landscape. Nevertheless, in the last few years, giant strides in CNS research have yielded significantly-improved understanding of the molecular underpinnings of the various pathological conditions of the brain, not least those associated with the death of neurones, including Parkinson’s and Alzheimer’s diseases. Accordingly, one pathway now known to be majorly involved in the induction of neuronal death is associated with the nuclear enzyme, poly (ADP-ribose) polymerase-1 (PARP-1), whose excessive activation generates a large amount of its polymer, poly (ADP-ribose) (PAR), which, in turn, causes an otherwise beneficial protein, normally resident in the mitochondria, the apoptosis-inducing factor (AIF), to exit its natural domain and enter the nucleus, where it causes large-scale DNA fragmentation and chromatin condensation, ultimately resulting in neuronal death. This review briefly explores the pathological cascade and suggests why targeting it in drug discovery - especially at the level of nuclear AIF translocation - is a rational and promising approach that may eventually deliver novel drugs for clinical use. In addition, the work illustrates how a clear knowledge of the spatio-temporal dynamics of molecular events is highly critical and, in fact, indispensable to a successful drug discovery and development campaign from the bench to the bedside, while at the same time highlighting the multi-disciplinary nature of the drug discovery enterprise.