The<i>Swiss Cheese</i>Mutant Causes Glial Hyperwrapping and Brain Degeneration in<i>Drosophila</i>

Kretzschmar, Doris; Hasan, Gaiti; Sharma, Sidhartha; Heisenberg, Martin; Benzer, Seymour

doi:10.1523/jneurosci.17-19-07425.1997

Cited by 232 publications

(258 citation statements)

References 46 publications

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“…Despite many common features, there appear to be species differences in the sequence of events between NTE inhibition and neurotoxicity. The Drosophila neurodegeneration gene swiss cheese encodes a neuronal protein involved in glial hyperwrapping and brain degeneration and homologous to human NTE, possibly relating it to OPIDN (46,47). The mouse NTE protein is 96% identical to the human NTE protein (46).…”

Section: Discussionmentioning

confidence: 99%

Evidence that mouse brain neuropathy target esterase is a lysophospholipase

Quistad

Barlow²,

Winrow³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

122

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Neuropathy target esterase (NTE) is inhibited by several organophosphorus (OP) pesticides, chemical warfare agents, lubricants, and plasticizers, leading to OP-induced delayed neuropathy in people (>30,000 cases of human paralysis) and hens (the best animal model for this demyelinating disease). The active site region of NTE as a recombinant protein preferentially hydrolyzes lysolecithin, suggesting that this enzyme may be a type of lysophospholipase (LysoPLA) with lysolecithin as its physiological substrate. This hypothesis is tested here in mouse brain by replacing the phenyl valerate substrate of the standard NTE assay with lysolecithin for an ''NTE-LysoPLA'' assay with four important findings. First, NTE-LysoPLA activity, as the NTE activity, is 41-45% lower in Nte-haploinsufficient transgenic mice than in their wild-type littermates. Second, the potency of six delayed neurotoxicants or toxicants as in vitro inhibitors varies from IC 50 0.02 to 13,000 nM and is essentially the same for NTE-LysoPLA and NTE (r 2 ‫؍‬ 0.98). Third, the same six delayed toxicants administered i.p. to mice at multiple doses inhibit brain NTE-LysoPLA and NTE to the same extent (r 2 ‫؍‬ 0.90). Finally, their in vivo inhibition of brain NTELysoPLA generally correlates with delayed toxicity. Therefore, OP-induced delayed toxicity in mice, and possibly the hyperactivity associated with NTE deficiency, may be due to NTE-LysoPLA inhibition, leading to localized accumulation of lysolecithin, a known demyelinating agent and receptor-mediated signal transducer. This mouse model has some features in common with OP-induced delayed neuropathy in hens and people but differs in the neuropathological signs and apparently the requirement for NTE aging.

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Section: Discussionmentioning

confidence: 99%

Evidence that mouse brain neuropathy target esterase is a lysophospholipase

Quistad

Barlow²,

Winrow³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

122

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“…ThioflavinS staining was performed following Fay et al (29). Transmission electron microscope analysis was performed as described (30).…”

Section: Methodsmentioning

confidence: 99%

Dissecting the pathological effects of human Aβ40 and Aβ42 in Drosophila : A potential model for Alzheimer's disease

Iijima

Liu

Chiang

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

446

441

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Accumulation of amyloid-␤ (A␤) peptides in the brain has been suggested to be the primary event in sequential progression of Alzheimer's disease (AD). Here, we use Drosophila to examine whether expression of either the human A␤40 or A␤42 peptide in the Drosophila brain can induce pathological phenotypes resembling AD. The expression of A␤42 led to the formation of diffused amyloid deposits, age-dependent learning defects, and extensive neurodegeneration. In contrast, expression of A␤40 caused only age-dependent learning defects but did not lead to the formation of amyloid deposits or neurodegeneration. These results strongly suggest that accumulation of A␤42 in the brain is sufficient to cause behavioral deficits and neurodegeneration. Moreover, Drosophila may serve as a model for facilitating the understanding of molecular mechanisms underlying A␤ toxicity and the discovery of novel therapeutic targets for AD. A lzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive decline in memory accompanied by histological changes, including neuronal loss and the formation of neurofibrillary tangles (NFTs) and senile plaques (1). The accumulation of amyloid-␤ (A␤)42 peptide, the major component of senile plaques, has been hypothesized to be the primary event in AD pathogenesis (2, 3). The strongest support for the A␤ hypothesis comes from genetic analyses of familial AD (FAD); most FAD mutations identified in A␤ precursor protein (APP), Presenilin1 (PS1) and Presenilin2 (PS2) genes appear to cause excessive accumulation of A␤42 (4). Secretion of A␤ peptides is a result of sequential cleavage of APP by ␤-secretase, a type I transmembrane glycosylated aspartyl protease, and ␥-secretase, a large protein complex that includes at least four proteins, Presenilins (PS1 or PS2), Nicastrin, Aph-1, and Pen-2 (for review, see ref. 5). The heterogeneity of ␥-secretase cleavage gives rise to a series of A␤ peptides, including the major species A␤40 and a smaller amount of A␤42.To study AD pathogenesis in vivo, a number of AD mouse models have been established and have successfully recapitulated AD-like phenotypes, including abundant amyloid deposits, astroglial activation, synaptic loss and dysfunction, behavioral abnormalities, and neurodegeneration (6-15). In addition to these mouse models, the model systems that allow highthroughput genetic screening will facilitate the discovery of genes involved in AD pathogenesis. Furthermore, one of the intriguing issues that have not been elucidated in these transgenic mice is the pathological roles of each specific A␤ species (i.e., A␤40 and A␤42), because currently available mouse models mainly rely on overexpression of APP.We use a Drosophila model (16) to compare the specific pathological roles of A␤40 and A␤42. In Drosophila, all components involved in the protein complex responsible for ␥-secretase activity are highly conserved (17), whereas ␤-secretase activity is absent or very low (18). An APP-like protein (APPL) is also present in flies, althou...

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“…Tissue-specific deletion of NTE in murine brain provoked severe neuropathologic symptoms in the hippocampus, thalamus, and cerebellum and led to disruption of the endoplasmic reticulum, vacuolation of nerve cell bodies, and abnormal reticular aggregates suggesting a central role of this enzyme in phospholipid metabolism in the nervous system (19). A similar role was indicated for the Drosophila orthologue Swiss Cheese (SWS) (20,21). SWS mutant flies show spongiform lesions within the CNS, glial hyperwrapping around neurons, and neuronal apoptosis.…”

mentioning

confidence: 85%

Identification of an Insulin-regulated Lysophospholipase with Homology to Neuropathy Target Esterase

Kienesberger

Lass

Preiss-Landl

et al. 2008

Journal of Biological Chemistry

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Neuropathy target esterase (NTE) is a member of the family of patatin domain-containing proteins and exhibits phospholipase activity in brain and cultured cells. NTE was originally identified as target enzyme for organophosphorus compounds that cause a delayed paralyzing syndrome with degeneration of nerve axons. Here we show that the structurally related murine protein NTErelated esterase (NRE) is a potent lysophospholipase. The enzyme efficiently hydrolyzes sn-1 esters in lysophosphatidylcholine and lysophosphatidic acid. No lipase activity was observed when triacylglycerols, cholesteryl esters, retinyl esters, phosphatidylcholine, or monoacylglycerol were used as substrates. Although NTE is predominantly expressed in the nervous system, we found the highest NRE mRNA levels in testes, skeletal muscle, cardiac muscle, and adipose tissue. Induction of NRE mRNA concentrations in these tissues during fasting suggested a nutritional regulation of enzyme expression and, in accordance with this observation, insulin reduced NRE mRNA levels in a dose-dependent manner in 3T3-L1 adipocytes. A green fluorescent protein-NRE fusion protein colocalized to the endoplasmic reticulum and lipid droplets. Thus, NRE is a previously unrecognized ER-and lipid droplet-associated lysophospholipase. Regulation of enzyme expression by the nutritional status and insulin suggests a role of NRE in the catabolism of lipid precursors and/or mediators that affect energy metabolism in mammals.

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TheSwiss CheeseMutant Causes Glial Hyperwrapping and Brain Degeneration inDrosophila

Cited by 232 publications

References 46 publications

Evidence that mouse brain neuropathy target esterase is a lysophospholipase

Evidence that mouse brain neuropathy target esterase is a lysophospholipase

Dissecting the pathological effects of human Aβ40 and Aβ42 in Drosophila : A potential model for Alzheimer's disease

Identification of an Insulin-regulated Lysophospholipase with Homology to Neuropathy Target Esterase

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