Influence of lysophospholipid hydrolysis by the catalytic domain of neuropathy target esterase on the fluidity of bilayer lipid membranes

Greiner, Aaron J.; Richardson, Rudy J.; Worden, R. Mark; Ofoli, Robert Y.

doi:10.1016/j.bbamem.2010.03.015

Cited by 19 publications

(6 citation statements)

References 49 publications

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“…In particular, lysoPLs affect the biophysical properties of membranes and influence the functions of membrane-embedded proteins [48]. They are related with several important processes in eukaryotes such as neurotransmitter release [49], regulation of the membrane fluidity [50], and phagocytosis [51]. Limited data exist for their function in bacteria; few examples include the E.…”

Section: Resultsmentioning

confidence: 99%

Structural and Functional Characterisation of TesA - A Novel Lysophospholipase A from Pseudomonas aeruginosa

et al. 2013

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TesA from Pseudomonas aeruginosa belongs to the GDSL hydrolase family of serine esterases and lipases that possess a broad substrate- and regiospecificity. It shows high sequence homology to TAP, a multifunctional enzyme from Escherichia coli exhibiting thioesterase, lysophospholipase A, protease and arylesterase activities. Recently, we demonstrated high arylesterase activity for TesA, but only minor thioesterase and no protease activity. Here, we present a comparative analysis of TesA and TAP at the structural, biochemical and physiological levels. The crystal structure of TesA was determined at 1.9 Å and structural differences were identified, providing a possible explanation for the differences in substrate specificities. The comparison of TesA with other GDSL-hydrolase structures revealed that the flexibility of active-site loops significantly affects their substrate specificity. This assumption was tested using a rational approach: we have engineered the putative coenzyme A thioester binding site of E. coli TAP into TesA of P. aeruginosa by introducing mutations D17S and L162R. This TesA variant showed increased thioesterase activity comparable to that of TAP. TesA is the first lysophospholipase A described for the opportunistic human pathogen P. aeruginosa. The enzyme is localized in the periplasm and may exert important functions in the homeostasis of phospholipids or detoxification of lysophospholipids.

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Section: Resultsmentioning

confidence: 99%

Structural and Functional Characterisation of TesA - A Novel Lysophospholipase A from Pseudomonas aeruginosa

et al. 2013

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“…Previously, LPC has been shown to directly enhance the formation of Aß(1–42) fibrils [ 47 , 48 ]. Except for protein fibrillization, the accumulation of lysoPLs in brain tissue elicits neurotoxic effects, through the release of proinflammatory molecules [ 49 ], astrocyte and microglial activation [ 50 ], and alterations in membrane organization/fluidity [ 51 ]. Our previous work showed that abnormal truncated tau induced inflammatory response in late stages of pathology [ 52 ] and therefore the gradual increase of LPC and LPE in brain tissue of Tg rats could be result of neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies

Olešová,

Dobešová,

Majerová

et al. 2024

J Neuroinflammation

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Background Accumulation of tau leads to neuroinflammation and neuronal cell death in tauopathies, including Alzheimer’s disease. As the disease progresses, there is a decline in brain energy metabolism. However, the role of tau protein in regulating lipid metabolism remains less characterized and poorly understood. Methods We used a transgenic rat model for tauopathy to reveal metabolic alterations induced by neurofibrillary pathology. Transgenic rats express a tau fragment truncated at the N- and C-terminals. For phenotypic profiling, we performed targeted metabolomic and lipidomic analysis of brain tissue, CSF, and plasma, based on the LC-MS platform. To monitor disease progression, we employed samples from transgenic and control rats aged 4, 6, 8, 10, 12, and 14 months. To study neuron-glia interplay in lipidome changes induced by pathological tau we used well well-established multicomponent cell model system. Univariate and multivariate statistical approaches were used for data evaluation. Results We showed that tau has an important role in the deregulation of lipid metabolism. In the lipidomic study, pathological tau was associated with higher production of lipids participating in protein fibrillization, membrane reorganization, and inflammation. Interestingly, significant changes have been found in the early stages of tauopathy before the formation of high-molecular-weight tau aggregates and neurofibrillary pathology. Increased secretion of pathological tau protein in vivo and in vitro induced upregulated production of phospholipids and sphingolipids and accumulation of lipid droplets in microglia. We also found that this process depended on the amount of extracellular tau. During the later stages of tauopathy, we found a connection between the transition of tau into an insoluble fraction and changes in brain metabolism. Conclusion Our results revealed that lipid metabolism is significantly affected during different stages of tau pathology. Thus, our results demonstrate that the dysregulation of lipid composition by pathological tau disrupts the microenvironment, further contributing to the propagation of pathology.

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“…Previously, LPC has been shown to directly enhance the formation of Aß(1-42) fibrils [43,44]. Except for protein fibrillization, the accumulation of lysoPLs in brain tissue elicits neurotoxic effects, through the release of proinflammatory molecules [45], astrocyte and microglial activation [46], and alterations in membrane organization/fluidity [47]. Our previous work showed that abnormal truncated tau induced inflammatory response in later stages of pathology [48], and therefore the gradual increase of LPC and LPE in brain tissue of Tg rats could be the result of progressive neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies

Olešová,

Dobešová,

Majerová

et al. 2023

Preprint

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Background Abnormal aggregation of tau protein that leads to brain inclusions is a common feature of neurodegenerative disorders called tauopathies. Recent evidence suggests the involvement of lipid metabolic deregulations in the pathogenesis of tauopathies. However, the role of tau protein in the regulation of lipid metabolism is much less characterized and not well understood. Methods We used a transgenic rat model for tauopathy to reveal metabolic alterations induced by neurofibrillary pathology. Transgenic rats express a tau fragment truncated at the N- and C-terminals. For phenotypic profiling, we performed targeted metabolomic and lipidomic analysis of brain tissue, CSF, and plasma, based on the LC-MS platform. To monitor disease progression, we employed samples from transgenic and control rats aged 4, 6, 8, 10, 12, and 14 months. To study neuron-glia interplay in lipidome changes induced by pathological tau we used well well-established multicomponent cell model system. Univariate and multivariate statistical approaches were used for data evaluation. Results We showed that tau has an important role in the deregulation of lipid metabolism. In the lipidomic study, pathological tau was associated with higher production of lipids participating in protein fibrillization, membrane reorganization, and inflammation. Interestingly, significant changes have been found in the early stages of tauopathy before the formation of high-molecular-weight tau aggregates and neurofibrillary pathology. Increased secretion of pathological tau protein in vivo and in vitro induced upregulated production of phospholipids and sphingolipids and accumulation of lipid droplets in microglia. During the later stages of tauopathy, we found a connection between the transition of tau into an insoluble fraction and changes in brain metabolism. The results showed that dysregulation of lipid composition by pathological tau leads to disruption of the microenvironment and further propagation of pathology. Conclusion Our results revealed that lipid metabolism is significantly affected during different stages of tau pathology and provide new evidence that supports the contribution of pathological tau proteins in individual lipid pathways. Our data suggests that biologically active membrane lipids such as phospholipids and sphingolipids could represent new potential next-generation therapeutic targets in tauopathies.

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Influence of lysophospholipid hydrolysis by the catalytic domain of neuropathy target esterase on the fluidity of bilayer lipid membranes

Cited by 19 publications

References 49 publications

Structural and Functional Characterisation of TesA - A Novel Lysophospholipase A from Pseudomonas aeruginosa

Structural and Functional Characterisation of TesA - A Novel Lysophospholipase A from Pseudomonas aeruginosa

Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies

Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies

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