The spinal muscular atrophies (SMAs), characterized by spinal cord motor neuron depletion, are among the most common autosomal recessive disorders. One model of SMA pathogenesis invokes an inappropriate persistence of normally occurring motor neuron apoptosis. Consistent with this hypothesis, the novel gene for neuronal apoptosis inhibitory protein (NAIP) has been mapped to the SMA region of chromosome 5q13.1 and is homologous with baculoviral apoptosis inhibitor proteins. The two first coding exons of this gene are deleted in approximately 67% of type I SMA chromosomes compared with 2% of non-SMA chromosomes. Furthermore, RT-PCR analysis reveals internally deleted and mutated forms of the NAIP transcript in type I SMA individuals and not in unaffected individuals. These findings suggest that mutations in the NAIP locus may lead to a failure of a normally occurring inhibition of motor neuron apoptosis resulting in or contributing to the SMA phenotype.

In inbred mouse strains, permissiveness to intracellular replication of Legionella pneumophila is controlled by a single locus (Lgn1), which maps to a region within distal Chromosome 13 that contains multiple copies of the gene baculoviral IAP repeat-containing 1 (Birc1, also called Naip; refs. 1-3). Genomic BAC clones from the critical interval were transferred into transgenic mice to functionally complement the Lgn1-associated susceptibility of A/J mice to L. pneumophila. Here we report that two independent BAC clones that rescue susceptibility have an overlapping region of 56 kb in which the entire Lgn1 transcript must lie. The only known full-length transcript coded in this region is Birc1e (also called Naip5).

Legionella pneumophila is an intracellular pathogen that causes Legionnaires’ disease in humans. Inbred mouse strains are uniformly resistant to L. pneumophila infection with the notable exception of A/J, where the chromosome 13 locus Lgn1 renders A/J macrophages permissive to L. pneumophila replication. The mouse Lgn1 region is syntenic with the spinal muscular atrophy (SMA) locus on human chromosome 5 and includes several copies of the neuronal apoptosis inhibitory protein (Naip) gene. We have analyzed a possible link among Lgn1, Naip, and macrophage function. RNA expression studies show that Naip (mostly copy 2) mRNA transcripts are expressed in macrophage-rich tissues, such as spleen, lung, and liver and are abundant in primary macrophages. Immunoblotting and immunoprecipitation analyses identify Naip protein expression in mouse macrophages and in macrophage cell lines RAW 264.7 and J774A. Interestingly, macrophages from permissive A/J mice express significantly less Naip protein than their nonpermissive C57BL/6J counterpart. Naip protein expression is increased after phagocytic events. Naip protein levels during infection with either virulent or avirulent strains of L. pneumophila increase during the first 6 h postinfection and remain elevated during the 48-h observation period. This enhanced expression is also observed in macrophages infected with Salmonella typhimurium. Likewise, an increase in Naip protein levels in macrophages is observed 24 h after phagocytosis of Latex beads. The cosegregation of Lgn1 and Naip together with the detected Naip protein expression in host macrophages as well as its modulation after phagocytic events and during intracellular infection make it an attractive candidate for the Lgn1 locus.

The neuronal apoptosis inhibitory protein (NAIP) is a member of a novel family of inhibitor of apoptosis (IAP) proteins. The IAP genes are highly conserved from baculovirus to metazoans and suppress apoptosis induced by a variety of triggers both in vitro and in vivo. Here we describe the generation and characterization of mice with the targeted deletion of NAIP1. We demonstrate that the NAIP1-deleted mice develop normally. However, the survival of pyramidal neurons in the hippocampus after kainic acid-induced limbic seizures is greatly reduced in the NAIP1 knock-out animals. Thus, although NAIP1 is not necessary for normal development of murine central nervous system, the endogenous NAIP1 is required for neuronal survival in pathological conditions. A poptosis plays a critical role in the regulation of cell death in the peripheral and central nervous system (CNS) both in the physiological settings and in the neurological disease. Dysregulation of apoptosis occurs in chronic neurodegenerations such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, as well as in epilepsy and ischemia (1). Spinal muscular atrophy (SMA) is a neurodegenerative disorder characterized by a progressive wasting of spinal cord motor neurons. Recently, we have proposed a link between inappropriate apoptosis and modulation of SMA severity. We have shown that the neuronal apoptosis inhibitory protein (NAIP) is deleted in a significant proportion of SMA patients (2). Full-length functional NAIP is absent in most individuals with type I SMA, and there exists a close correlation between the regional distribution of NAIP in the CNS and the neurodegenerative alterations in SMA (3). These observations are consistent with the neurodegenerative character of SMA. Although the causative gene involved in SMA is believed to be the SMN (survival motor neuron) gene (4), the role of NAIP in SMA is proposed to be a modulating one, exacerbating the severity of the disease (5).The NAIP gene is a member of a recently identified family of intrinsic cellular regulators of apoptosis, the inhibitor of apoptosis (IAP) gene family (6). The IAP genes were initially discovered in baculoviruses, but their homologs have since been identified in other viruses, insects, birds, and mammals, suggesting a common evolutionary origin (7). Remarkably, IAP proteins suppress apoptosis induced by a diversity of triggers that is greater than that reported for any other antiapoptotic genes including the bcl-2 family (8). The mode of action of the IAP genes is believed to be by direct binding and inhibition of the key caspases and procaspases (primarily caspase 3 and 7) (9-12). Significantly, we have shown that transient forebrain ischemia selectively elevates levels of NAIP in neurons, which are resistant to ischemic injury. Moreover, the ectopic overexpression of NAIP in the CNS attenuated neuronal damage inflicted by transient forebrain ischemia, suggesting that NAIP plays a key role in neuroprotection (13).The role of the IAP genes in the control and mo...