Disease relevance of NLRP1

• Up-regulation of NALP1 was also observed in a model of transient focal ischemia induced by middle cerebral artery occlusion [1].
• The apoptotic marker, NALP1, was overexpressed (> 50-fold, P < 0.05) in the appendicitis-associated and malignant appendiceal carcinoids but was significantly decreased (> 10-fold, P < 0.05) in the goblet cell adenocarcinoids [2].
• Notably, the expression of NALP1 was significantly increased in the bone marrow blast cell population of some patients with acute leukaemia, but not among tissue samples from thyroid and renal cancer [3].
• NALP1 in vitiligo-associated multiple autoimmune disease [4].
• To pinpoint the exact region responsible we have carried out assays of toxicity and physicochemical properties on smaller fragments of NAC [5].

Psychiatry related information on NLRP1

• In Alzheimer's disease, synuclein/NAC (non-amyloid beta component of Alzheimer's disease amyloid) proteins are found in presynaptic cholinergic nerve terminals that degenerate early in Alzheimer's disease, and they are also found closely linked to beta-amyloid fibrils in senile plaques [6].

High impact information on NLRP1

• Like the structurally related apoptotic protease-activating factor-1 (APAF-1), which is responsible for the activation of caspase-9, the NALP1 protein forms a large, signal-induced multiprotein complex, the inflammasome, resulting in the activation of pro-inflammatory caspases [7].
• The NALP3 protein is homologous to NALP1, which is a component of the inflammasome, a molecular platform that activates the proinflammatory caspases-1 and -5 [8].
• Several genes related to nitrogen metabolism, especially those regulated by the NtrC and NAC proteins and transcribed via the varsigma(54) alternative sigma factor, were suppressed by both normal and oxidase-deficient neutrophils [9].
• These data unveil another level of complexicity in the regulation of intracellular innate immunity and may have important implications for the molecular understanding of NOD/NALP protein-driven disease pathophysiology [10].
• The recent determination of the DNA and protein binding NAC domain structure offers insight into the molecular functions of the protein family [11].

Chemical compound and disease context of NLRP1

• The neuron-specific toxicity of NAC fibrils was indicated also by an increased release of lactate dehydrogenase from the cells [12].
• Reducing H2O2 through overexpression of catalase or treatment of cells with NAC or BHA did not have an effect on TNF-induced chromosomal aberration [13].
• In the current study, the protective effects of two antioxidants, acetyl-L-carnitine (ALCAR) and N-L-acetylcysteine (NAC), were investigated in a chinchilla model of hearing loss resulting from impulse noise [14].

Biological context of NLRP1

• Also described here are studies on the mechanism of action studies including deletion analyses and investigations of nucleotide binding, which begin to elucidate a regulatory function for NALP1 in neuronal apoptosis [1].
• We report here that NALP1 gene expression was induced in primary cerebellar granule neurons (CGN) upon injury [1].
• Expression of recombinant NALP1 stimulated cell death in both HeLa cells and CGN by an apoptotic mechanism, demonstrated by the induction of apoptotic nuclear morphology and activation of the apoptotic enzyme caspase-3 [1].
• Conditional logistic-regression analysis of NALP1 SNPs indicated that at least two variants contribute independently to the risk of disease [4].
• Fine-scale association mapping with the use of DNA from affected families and additional SNPs in and around NALP1 showed an association of specific variants with vitiligo alone, with an extended autoimmune and autoinflammatory disease phenotype, or with both [4].

Anatomical context of NLRP1

• We investigated the biological consequence of over-expression of NALP1 in both HeLa cells and in CGN [1].
• RESULTS: Association analyses resulted in our identifying as a candidate gene NALP1, which encodes NACHT leucine-rich-repeat protein 1, a regulator of the innate immune system [4].
• In the present study, we report that expression of NALP1 is absent from CD34+ haematopoietic blast cells, and its levels are upregulated upon differentiation of CD34+ cells into granulocytes and to a lesser extent into monocytes [3].
• In peripheral blood cells, the highest levels of NALP1 were observed in CD3+ (T-lymphocytes), CD15+ (granulocytes) and CD14+ (monocytes) cell populations [3].
• Thus NALP1 is transcriptionally regulated by CREB in myeloid cells, a mechanism that may contribute to modulate the response of these cells to pro-inflammatory stimuli [3].

Associations of NLRP1 with chemical compounds

• A certain class of the NAC transcription factors is important for growth suppression at the boundary, and auxin and microRNAs participate in boundary formation by regulating NAC gene expression [15].
• MGO and cisplatin increased PKCdelta activity by 4-fold, and this effect was blocked by the PKCdelta inhibitor rottlerin but not by NAC [16].
• Mangiferin, similar to the other known antioxidants, NAC and PDTC, inhibits TNF-induced reactive oxygen intermediate (ROI) generation [17].
• Exposure to NAC fibrils increased also the nuclear translocation of nuclear factor kappa B (NF-kappaB) and enhanced its DNA-binding activity, which was inhibited by PG and BPN more efficiently in neurons than in astrocytes [12].
• NAC and alpha-synuclein both form beta-sheet structures upon ageing, aggregate to form fibrils, and are neurotoxic [5].

Other interactions of NLRP1

• Recently, the 3D structures determined by NMR of NALP1 and ASC PAAD domain, members of the PAAD family, have shown that it is composed of a 6 helix bundle as with other death domain family members [18].
• Further, a transition from complete disorder to order of the alpha2-alpha3 loop upon binding, as suggested for NALP1, is unlikely to be a common attribute of pyrin domain interactions [19].
• NALP1 is a transcriptional target for cAMP-response-element-binding protein (CREB) in myeloid leukaemia cells [3].

Analytical, diagnostic and therapeutic context of NLRP1

• The duration of pain relief following NALP (59.65 +/- 68.72 days) was significantly longer compared with that recorded following electrical stimulation (2.97 +/- 2.58 days) [20].
• Circular dichroism and infrared spectroscopies suggested that the OPR, R5, and Q50 motifs formed an antiparallel beta sheet as well as a random coil, whereas the R2 and NAC motifs mainly formed random coils [21].
• We examined the interactions between apoE and NAC and found that apoE bound synthetic NAC, forming a complex that resisted reducing agents and separation on SDS-PAGE [22].
• Less hair cell loss was also observed in the ALCAR and NAC groups than in the control group [14].

References