Degeneracija aksona i esteraza povezana s neuropatskim djelovanjem organofosfornih spojeva - pregled

This brief review summarises recent observations which suggest a possible mechanism for organophosphateinduced delayed neuropathy (OPIDN). Neuropathy target esterase (NTE) has been shown to deacylate endoplasmic reticulum (ER) membrane phosphatidylcholine (PtdCho). Raised levels of PtdCho are present in the brains of swiss cheese/NTE mutant Drosophila together with abnormal membrane structures, axonal and dendritic degeneration and neural cell loss. Similar vacuolated pathology is found in the brains of mice with brain-specific deletion of the NTE gene and, in old age, these mice show clinical and histopathological features of neuropathy resembling those in wild-type mice chronically dosed with tri-ortho-cresylphosphate. It is suggested that OPIDN results from the loss of NTE’s phospholipase activity which in turn causes ER malfunction and perturbation of axonal transport and glial-axonal interactions.Ovim se kratkim pregledom razmatraju nedavna opažanja koja upućuju na mogući mehanizam odgođene neuropatije uzrokovane organofosfatima (engl. organophosphate-induced delayed neuropathy, krat. OPIDN). Za esterazu povezanu s neuropatskim djelovanjem organofosfornih spojeva (engl. neuropathy target esterase, krat. NTE) dokazano je da deacilira fosfatidilkolin (PtdCho) membrane endoplazmatskog retikuluma (ER). Povišene razine PtdCho prisutne su u mozgu swiss cheese/NTE mutanta mušice Drosophila uz abnormalne membranske strukture, degeneraciju aksona i dendrita te gubitak neurona. Slična je vakuolarna patologija zamijećena u mozgu miševa u kojih je obrisan NTE gen u mozgu te koji u starijoj dobi pokazuju kliničke i histopatološke znakove neuropatije koja je slična onoj u običnih miševa kronično tretiranih tri-ortho-krezilfosfatom. Odgođena neuropatija uzrokovana organofosfatima mogla bi biti posljedicom prestanka djelovanja fosfolipaze NTE, što potom uzrokuje zatajenje endoplazmatskog retikuluma i smetnje u prijenosu signala putem aksona te interakcije između glija i aksona

NTE1-encoded Phosphatidylcholine Phospholipase B Regulates Transcription of Phospholipid Biosynthetic Genes*

The Saccharomyces cerevisiae NTE1 gene encodes an evolutionarily conserved phospholipase B localized to the endoplasmic reticulum (ER) that degrades phosphatidylcholine (PC) generating glycerophosphocholine and free fatty acids. We show here that the activity of NTE1-encoded phospholipase B (Nte1p) prevents the attenuation of transcription of genes encoding enzymes involved in phospholipid synthesis in response to increased rates of PC synthesis by affecting the nuclear localization of the transcriptional repressor Opi1p. Nte1p activity becomes necessary for cells growing in inositol-free media under conditions of high rates of PC synthesis elicited by the presence of choline at 37 °C. The specific choline transporter encoded by the HNM1 gene is necessary for the burst of PC synthesis observed at 37 °C as follows: (i) Nte1p is dispensable in an hnm1Δ strain under these conditions, and (ii) there is a 3-fold increase in the rate of choline transport via the Hnm1p choline transporter upon a shift to 37 °C. Overexpression of NTE1 alleviated the inositol auxotrophy of a plethora of mutants, including scs2Δ, scs3Δ, ire1Δ, and hac1Δ among others. Overexpression of NTE1 sustained phospholipid synthesis gene transcription under conditions that normally repress transcription. This effect was also observed in a strain defective in the activation of free fatty acids for phosphatidic acid synthesis. No changes in the levels of phosphatidic acid were detected under conditions of altered expression of NTE1. Consistent with a synthetic impairment between challenged ER function and inositol deprivation, increased expression of NTE1 improved the growth of cells exposed to tunicamycin in the absence of inositol. We describe a new role for Nte1p toward membrane homeostasis regulating phospholipid synthesis gene transcription. We propose that Nte1p activity, by controlling PC abundance at the ER, affects lateral membrane packing and that this parameter, in turn, impacts the repressing transcriptional activity of Opi1p, the main regulator of phospholipid synthesis gene transcription