Omega-3 and omega-6 fatty acids suppress ER- and oxidative stress in cultured neurons and neuronal progenitor cells from mice lacking PPT1

Abstract

Reactive oxygen species (ROS) damage to brain lipids, carbohydrates, proteins, and DNA may contribute to neurodegeneration. We previously reported that ER-and oxidative stress cause neuronal apoptosis in infantile neuronal ceroid lipofuscinosis (INCL), a lethal neurodegenerative storage disease, caused by palmitoyl-protein thioesterase-1(PPT1)-deficiency. Polyunsaturated fatty acids (PUFA) are essential components of cell membrane phospholipids in the brain and excessive ROS may cause oxidative damage PUFA leading to neuronal death. Using cultured neurons and neuroprogenitor cells from mice lacking Ppt1, which mimic INCL, we demonstrate that Ppt1-deficient neurons and neuroprogenitor cells contain high levels of ROS, which may cause perxidation of PUFA and render them incapable of providing protection against oxidative stress. We tested whether treatment of these cells with omega-3 or omega-6 PUFA protects the neurons and neuroprogenitor cells from oxidative stress and suppress apoptosis. We report here that both omega-3 and omega-6 fatty acids protect the Ppt1-deficient cells from ER-as well as oxidative stress and suppress apoptosis. Our results suggest that PUFA supplementation may have neuroprotective effects in INCL. KeywordsINCL; palmitoyl-protein thioesterase-1; Batten disease; Neurodegenaration; ER-stress; Oxidative stress; Apoptosis; PUFA The nervous system is highly enriched with an enormous variety of complex lipids, among which polyunsaturated fatty acids (PUFAs) predominate [reviewed in 1]. Despite their abundance in the mammalian brain, de novo synthesis of PUFAs such as arachidonic acid (AA) and docosahexanoic acid (DHA) does not occur. Thus, the diet is the sole source of these fatty acids or their precursors [1]. Previous studies have established the critical roles of PUFAs in the development of the nervous system. Moreover, nearly 50% of the fatty acids * To whom all correspondence should addressed at: mukherja@exchange.nih.gov.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. . Thus, even though the PUFA levels are the same in normal and PPT1-deficient brains, the highly oxidative environment present in the brain of INCL patients and in that of the Ppt1-KO mice these lipids may not be adequate to protect the neurons from oxidative stress. Therefore, we hypothesized that omega-3 and omega-6 fatty acids may have neuroprotective effects in Ppt1-deficient cells. NIH Public AccessIn the present study, we analyzed cultured PPT1-deficient neurons and neuronal progenitor cells derived from the fetal brain tissues of Ppt1-KO mice. We also explored the effe...

Lack of phosphatidylethanolamine N-methyltransferase alters hepatic phospholipid composition and induces endoplasmic reticulum stress

“…For example, increased incorporation of the saturated fatty acid, palmitate, into ER lipids induces ER stress in cells [38]. In contrast, polyunsaturated fatty acids suppress ER stress [39]. Our data show that even in chow-fed mice, the lack of PEMT reduces the molar ratio of PC/PE in hepatic ER coincident with the induction of ER stress, but does not increase hepatic TG content (Fig.…”

Impact of the carotenoid astaxanthin on phagocytic capacity and ROS/RNS production of human neutrophils treated with free fatty acids and high glucose

“…Hussein and coworkers [25] also found an increase in NO• production associated with a reduction of the arterial blood pressure in spontaneously hypertensive rats, suggesting an antihypertensive role of ASTA. Recently, Kim and colleagues [67] found that ASTA reduced the activation of the transcription factor NF-κB and decreased the IL-6 production in microglial cells. Since NFκB is the most important pathway in immune cells, responsible of inducing NO• production by inducing iNOS expression, we can speculate that ASTA can promote a NF-κB activation which leads to an increase in NO• production.…”

Inhibition of Choline Acetyltransferase as a Mechanism for Cholinergic Dysfunction Induced by Amyloid-β Peptide Oligomers

“…The fact that the number of unsaturations is relevant for the protective effect supports the idea that direct reaction of PUFAs with ROS underlies the protective mechanism. However, indirect protective pathways cannot be ruled out because PUFAs are involved in complex intracellular signaling in the nervous system, promoting neuroprotection through modulation of inflammatory responses (43,44).…”