Disease relevance of NAIP

• It has been proposed that homozygous loss of SMNT is the primary cause of spinal muscular atrophy while the loss of NAIP and perhaps other genes primarily affects the severity of disease manifestation [1].
• Neuronal apoptosis inhibitory protein (NAIP)-like immunoreactivity in brains of adult patients with Down syndrome [2].
• Significant increase in the number of the SMN2 gene copies in an adult-onset Type III spinal muscular atrophy patient with homozygous deletion of the NAIP gene [3].
• Here we demonstrate a NAIP-mediated inhibition of apoptosis induced by a variety of signals, and have identified three additional human complementary DNAs and a Drosophila melanogaster sequence that are also homologous to the baculovirus IAPs [4].
• DISCUSSION: Alterations in C/CAAT enhancer binding protein alpha and neuronal apoptosis inhibitory protein expression occurred in human adipose stromal-vascular cells after weight loss in a pilot study of 10 patients [5].

Psychiatry related information on NAIP

• We assessed NAIP, XIAP, and cIAP-2 protein levels in the entorhinal cortex of non-demented, cognitively impaired and Alzheimer's disease cases [6].

High impact information on NAIP

• The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy [7].
• 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 [7].
• 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 [7].
• Although NAIP protein is known to have an anti-apoptotic function, the function of SMN has been unclear and it shows no significant sequence similarity to any other protein [8].
• In newborn rats, GDNF regulates endogenous levels of XIAP and NAIP in motor neurons after sciatic nerve axotomy [9].

Biological context of NAIP

• Interestingly, and in contrast to the X-chromosome-linked inhibitor of apoptosis protein (XIAP), NAIP-mediated inhibition of caspase-9 was not countered by a peptide containing an amino-terminal IAP binding motif (IBM) [10].
• Study of survival of motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) gene deletions in SMA patients [11].
• In the view of scarcity of genotype and phenotype correlation data from India, this study has been undertaken to determine that correlation in SMA patients by using the SMN and NAIP genes and two polymorphic markers C212 and C272 located in this region [12].
• Taken together with our previous data, we may reasonably hypothesize that the SMN2 gene copy number is more critical in determining the severity of the disease compared to the NAIP genotype [3].
• In the period 1998-2000 almost all new cases of childhood spinal muscular atrophy (SMA) in addition to those from our database were studied for possible deletion of SMN gene (exons 7 a 8) and NAIP (exons 5 a 6) [13].

Anatomical context of NAIP

• These molecules can prevent apoptosis in vitro and the over-expression of NAIP can decrease ischemic damage in the hippocampus [14].
• The goal of our experiments was to determine whether administration of NAIP, HIAP1 and HAIP2 could rescue motoneurons following axotomy of a peripheral nerve [14].
• NAIP-like immunoreactivity was determined in four different regions of cerebral cortex and cerebellum in 9 adult DS patients with Alzheimer-like neuropathologic lesions, 9 Alzheimer disease (AD) patients as compared to 9 controls [2].
• In contrast, NAIP mRNA was not detectable, and cIAP2 was found at the mRNA and protein levels in only 34 (56%) and 5 (8%) of the 60 tumor cell lines analyzed, respectively [15].
• As for age-related changes, the expression of cIAP2 in normal mucosa and moderately differentiated adenocarcinoma was stronger in the elderly group than the young group ( p<0.05, respectively), and NAIP expression in well-differentiated adenocarcinoma was higher in the young group than the elderly group ( p<0.05) [16].

Associations of NAIP with chemical compounds

• In neuronal cell lines NSC-34 and Neuro-2a, over-expression of the BIR domains of NAIP (NAIP-BIR1-3) counteracted the calcium-induced cell death induced by ionomycin and thapsigargin [17].
• Cisplatin decreased NAIP and survivin mRNAs in the same cells [18].
• IB-MECA 100 microM downregulated HIAP1, NAIP and survivin mRNAs in HL-60, but not in HL-60R cells [19].
• The cytotoxic interactions between curcumin and these agents were accompanied by synergistic (in particular with cisplatin) or additive effects of decrease in the expression of different genes, including c-myc, Bcl-X(L), c-IAP-2, NAIP and XIAP [20].
• These observations suggest that the powerful effects of PAX2 on renal branching morphogenesis and final nephron number may be mediated by activation of Naip which then suppresses apoptosis in UB cells [21].

Physical interactions of NAIP

• Consistent with this observation was the failure of Smac protein to interact with the NAIP BIR domains [10].
• NAIP interacts with hippocalcin and protects neurons against calcium-induced cell death through caspase-3-dependent and -independent pathways [17].

Regulatory relationships of NAIP

• A dopamine D4 receptor antagonist attenuates ischemia-induced neuronal cell damage via upregulation of neuronal apoptosis inhibitory protein [22].

Other interactions of NAIP

• Here we report that two other members of the IAP family, NAIP and ML-IAP, both activate JNK1 [23].
• Both SMN1 and NAIP genes showed homozygous absence in 76% and 31% respectively in proximal SMA patients [11].
• It also decreased interleukin 6 (IL-6), NAIP and, after 16 h of exposure to the higher concentration tested (10 microg/ml), c-IAP-1 mRNA levels [24].
• In this report, we examined the interaction of various regions of NAIP with caspase-9 and Smac [10].
• Recombinant c-IAP-1 and c-IAP-2 also inhibited the activity of caspases-3 and -7 in vitro, with estimated Kis of <=0.1 microM, whereas NAIP did not [25].

Analytical, diagnostic and therapeutic context of NAIP

• The administration of an adv-NAIP, adv-HIAP1 and adv-HIAP2 rescued 30-40% of motoneurons at one week after sciatic axotomy [14].
• Furthermore, RT-PCR analysis reveals internally deleted and mutated forms of the NAIP transcript in type I SMA individuals and not in unaffected individuals [7].
• We examined the endogenous expression of four members of the IAP family, X chromosome-linked IAP (XIAP), rat IAP1 (RIAP1), RIAP2, and neuronal apoptosis inhibitory protein (NAIP), by semiquantitative reverse PCR and immunoblot analysis in cultured cerebellar granule neurons [26].
• Prenatal diagnosis of childhood proximal spinal muscular atrophy (SMA) is carried out by the detection of homozygous deletions of survival motor neuron (SMN; exons 7 and 8) and neuronal apoptosis inhibitory protein (NAIP; exons 5 and 6) genes located in 5q13 chromosomal region [27].
• These data suggest that the NAIP upregulating compound, L-745,870, has therapeutic potential in acute ischemic disorders and that our NAIP-ELISA-based drug screening may facilitate the discovery of novel neuroprotective compounds [22].

References