It is now well established that cellular suicide (apoptosis or programmed cell death) is central to a number of physiological cellular processes and is essential in the maintenance of homeostasis and survival of multicellular organisms. Equally, or perhaps even more important is the role of apoptosis in the pathogenesis of many human diseases. Early interest largely focussed on the role of abnormally low levels of apoptosis as a contributory factor in the development of various cancer and hence a large number of therapeutic candidates able to stimulate apoptosis have been developed. The therapeutic benefit of such molecules has however been suboptimal due to a number of factors. More recently a family of proteins termed the "Inhibitor of Apoptosis Proteins" (IAP) family has however been identified and targeting members of this family offer a more targeted and more effective approach to the therapeutic control of apoptosis. As discussed in our full analysis of this field (click here) members of the IAP family have also been strongly implicated in neurodegenerative disorders as well as cancer. The targeted inhibition of IAPs such as NIAP may therefore offer new treatments for conditions such as stroke, multiple sclerosis, and motor neuron disease. NIAP is one of 8 known IAPs (other proteins include XIAP, cIAP-1 and cIAP-2) and was originally discovered because of its deletion in infantile spinal muscular atrophy (SMA), a childhood genetic disorder characterized by motor neuron loss and progressive paralysis with muscular atrophy. South Korean researchers have recently cloned rat NAIP that shows 78% homology to human NAIP and 86% homology to the murine counterpart. Rat NAIP was highly expressed in the areas innervated by glutamatergic neurons after kainic acid injection. Immunohistological investigation narrowed expression down to neuronal subpopulations in the retinal ganglion, cerebral cortex, hippocampus, basal forebrain, thalamus, areas of midbrain, Purkinje cells of the cerebellum, and motor neurons in the spinal cord. Increased immunoreactivity of glutamatergic neurons was also observed broadly in the CNS after kainic acid treatment. This study provides additional evidence to support the concept that NAIP is regulated in response to excessive stimuli or injuries in rat CNS, and these results are compatible with an anti-apoptotic role of NAIP in various neurodegenerative conditions including head injury, seizures, stroke and motor neuron disease.

It has already been demonstrated that the survival of pyramidal neurons in the hippocampus after kainic acid-induced limbic seizures is greatly reduced in NAIP1 or XIAP knock-out mice supporting a role for IAPs in neuroprotection. Moreover, in a ground-breaking study overexpression of NAIP1 or XIAP is able to confer resistance to ischemic death in the rat hippocampus. In addition to limiting the death of central neurons, gene transfer of NAIP, cIAP-1 or cIAP-2 is also able to reduce motor neuron death. Likewise XIAP overexpression resulted in a significant protection of retinal ganglion cells and optic nerve survival. These experiments demonstrate that IAP family proteins may offer a new therapeutic approach to a wide variety of neurodegenerative disorders.

Entry date February, 2003

Adapted from Shin et al, Neurochem Int 2003 May;42(6):481-91 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk