Neuropathy Target Esterase Gene Mutations Cause Motor Neuron Disease

Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 03/2008; 82(3):780-5. DOI: 10.1016/j.ajhg.2007.12.018
Source: PubMed


The possibility that organophosphorus (OP) compounds contribute to motor neuron disease (MND) is supported by association of paraoxonase 1 polymorphisms with amyotrophic lateral sclerosis (ALS) and the occurrence of MND in OP compound-induced delayed neuropathy (OPIDN), in which neuropathy target esterase (NTE) is inhibited by organophosphorylation. We evaluated a consanguineous kindred and a genetically unrelated nonconsanguineous kindred in which affected subjects exhibited progressive spastic paraplegia and distal muscle wasting. Affected subjects resembled those with OPIDN and those with Troyer Syndrome due to SPG20/spartin gene mutation (excluded by genetic linkage and SPG20/spartin sequence analysis). Genome-wide analysis suggested linkage to a 22 cM homozygous locus (D19S565 to D19S884, maximum multipoint LOD score 3.28) on chromosome 19p13 to which NTE had been mapped (GenBank AJ004832). NTE was a candidate because of its role in OPIDN and the similarity of our patients to those with OPIDN. Affected subjects in the consanguineous kindred were homozygous for disease-specific NTE mutation c.3034A-->G that disrupted an interspecies conserved residue (M1012V) in NTE's catalytic domain. Affected subjects in the nonconsanguineous family were compound heterozygotes: one allele had c.2669G-->A mutation, which disrupts an interspecies conserved residue in NTE's catalytic domain (R890H), and the other allele had an insertion (c.2946_2947insCAGC) causing frameshift and protein truncation (p.S982fs1019). Disease-specific, nonconserved NTE mutations in unrelated MND patients indicates NTE's importance in maintaining axonal integrity, raises the possibility that NTE pathway disturbances contribute to other MNDs including ALS, and supports the role of NTE abnormalities in axonopathy produced by neuropathic OP compounds.

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    • "In addition, a genetic study has implicated NTE mutations with motor neuron disease (Rainier et al., 2008), whereas our study and those of others (Kaushik et al., 2005) point to a role of NTE in SBS and CFS. Futhermore, mice heterozygous Nte allele (Nte1/– ) showed that a minor reduction in Nte activity can lead to a possible neuronal hyperactivity in mice (Winrow et al., 2003). "
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    ABSTRACT: Sick building syndrome (SBS) is a set of several clinically recognizable symptoms reported by occupants of a building without a clear cause. Neuropathy target esterase (NTE) is a membrane bound serine esterase and its reaction with organophosphates (OPs) can lead to OP-induced delayed neuropathy (OPIDN) and nerve axon degeneration. The aim of our study was to determine whether there was a difference in NTE activity in the peripheral blood mononuclear cells (PBMCs) of Japanese patients with SBS and healthy controls and whether PNPLA6 (alias NTE) gene polymorphisms were associated with SBS. We found that the enzymatic activity of NTE was significantly higher (P < 0.0005) in SBS patients compared with controls. Moreover, population with an AA genotype of a single nucleotide polymorphism (SNP), rs480208, in intron 21 of the PNPLA6 gene strongly reduced the activity of NTE. Fifty-eight SNP markers within the PNPLA6 gene were tested for association in a case-control study of 188 affected individuals and 401 age-matched controls. Only one SNP, rs480208, was statistically different in genotype distribution (P = 0.005) and allele frequency (P = 0.006) between the cases and controls (uncorrected for testing multiple SNP sites), but these were not significant by multiple corrections. The findings of the association between the enzymatic activity of NTE and SBS in Japanese show for the first time that NTE activity might be involved with SBS. © 2013 Wiley Periodicals, Inc. Environ Toxicol, 2013.
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    • "In contrast, brain specific NTE knock-out mice survive into adulthood and show a strikingly similar phenotype to sws mutants, including vacuolization, abnormal myelin figures, and neuronal death [21]. Mutations in human NTE cause a Hereditary Spastic Paraplegia, now called NTE-related Motor-Neuron Disorder (NTE-MND), that is characterized by progressive spastic weakness starting in childhood [22]. Although these mutations have been shown to reduce the enzymatic activity of NTE in these patients, a similar reduction was found in asymptomatic subjects that are heterozygous for an insertion that deletes the phospholipase domain [23]. "
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    ABSTRACT: Organophosphate-induced delayed neuropathy (OPIDN) is a Wallerian-type axonopathy that occurs weeks after exposure to certain organophosphates (OPs). OPs have been shown to bind to Neuropathy Target Esterase (NTE), thereby inhibiting its enzymatic activity. However, only OPs that also induce the so-called aging reaction cause OPIDN. This reaction results in the release and possible transfer of a side group from the bound OP to NTE and it has been suggested that this induces an unknown toxic function of NTE. To further investigate the mechanisms of aging OPs, we used Drosophila, which expresses a functionally conserved orthologue of NTE named Swiss Cheese (SWS). Treating flies with the organophosporous compound tri-ortho-cresyl phosphate (TOCP) resulted in behavioral deficits and neurodegeneration two weeks after exposure, symptoms similar to the delayed effects observed in other models. In addition, we found that primary neurons showed signs of axonal degeneration within an hour after treatment. Surprisingly, increasing the levels of SWS, and thereby its enzymatic activity after exposure, did not ameliorate these phenotypes. In contrast, reducing SWS levels protected from TOCP-induced degeneration and behavioral deficits but did not affect the axonopathy observed in cell culture. Besides its enzymatic activity as a phospholipase, SWS also acts as regulatory PKA subunit, binding and inhibiting the C3 catalytic subunit. Measuring PKA activity in TOCP treated flies revealed a significant decrease that was also confirmed in treated rat hippocampal neurons. Flies expressing additional PKA-C3 were protected from the behavioral and degenerative phenotypes caused by TOCP exposure whereas primary neurons were not. In addition, knocking-down PKA-C3 caused similar behavioral and degenerative phenotypes as TOCP treatment. We therefore propose a model in which OP-modified SWS cannot release PKA-C3 and that the resulting loss of PKA-C3 activity plays a crucial role in developing the delayed symptoms of OPIDN but not in the acute toxicity.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "Retinol and related retinoid compounds play key roles in the body including supporting vision (Palczewski 2011), regulating epithelial cell growth and differentiation (Long et al. 2010), contributing to the growth of bone tissue (Oki et al. 2008), immune function (Pino-Lagos et al. 2010) and the activation of tumor suppressor genes (Ye et al. 2009). This retinol-ester metabolic role is in contrast to functions reported for other PNPLA-like enzymes including ATGL (or adipose triglyceride lipase) in triglyceride hydrolysis in adipocyte and non-adipocyte lipid droplets (Zimmermann et al. 2004; Haemmerle et al. 2011); PNPLA3 in contributing to hepatic fat metabolism and nonalcoholic fatty liver disease (Romeo et al. 2008); PNPLA6 (or neuropathy target esterase) which contributes to membrane lipid homeostasis and assists in maintaining axonal integrity (Zaccheo et al. 2004; Rainier et al. 2008); and PNPLA8 which serves as a calcium-independent phospholipase A2 and catalyzes the hydrolysis of membrane phospholipids (Tanaka et al. 2000; Mancuso et al. 2000). PNPLA4 and other members of the PNPLA-like enzymes belong to the patatin family of acyl hydrolases whose proteins are characterized by a conserved amino acid sequence of Gly-X-Ser-X-Gly at their active sites, a Ser- Asp catalytic dyad (Ser43/Asp163 for human PNPLA4) (Rydel et al. 2003; Holmes 2012) instead of the Ser-His- Asp/Glu triad reported for other lipases (Cygler and Schrag 1997) and an oxy-anion 'hole' providing access to the active site (Rydel et al. 2003). "
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    ABSTRACT: At least eight families of mammalian patatinlike phospholipase domain-containing proteins (PNPLA) (E.C. catalyse the hydrolysis of triglycerides, including PNPLA4 (alternatively PLPL4 or GS2), which also acts as a retinol transacylase and participates in retinolester metabolism in the body. Bioinformatic methods were used to predict the amino acid sequences, secondary and tertiary structures and gene locations for PNPLA4 genes and encoded proteins using data from several vertebrate genome projects. PNPLA4 genes were located on the X-chromosome for the eutherian mammalian genomes examined. Opossum (marsupial), chicken, anole lizard, clawed toad, zebrafish and lancelet PNPLA4 genes were also identified. Most vertebrate PNPLA4 genes typically contained six coding exons whereas the lancelet PNPLA4 gene contained five coding exons. PNPLA4 subunits were the smallest among the PNPLA-like proteins examined containing 252-255 residues, shared >64 % sequence identities and key amino acid residues and predicted motifs, including 'patatin' (residues 6-176); putative catalytic dyad active site residues, Ser43 and Asp163; oxy-anion 'hole' residues (10-15); and conserved serine residues, which may perform structural roles for this enzyme. Predicted tertiary structures for PNPLA4 'patatin' were similar to those reported for potato 'patatin', suggesting that it is strongly conserved during evolution. Human PNPLA4 contained a CpG49 island within the gene promoter, a miRNA-186 binding site within the mRNA 30-noncoding region for the PNPLA4b isoform and exhibited wide tissue expression at a higher than average level. These and previous studies of vertebrate PNPLA-like gene families have suggested that PNPLA4 is an ancient gene in evolution which has resulted from a duplication of an ancestral invertebrate ATGL-like gene (encoding adipose triglyceride lipase).
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