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Nuclear Lipids in the Nervous System: What they do in Health and Disease

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Abstract

In the last 20 years it has been widely demonstrated that cell nucleus contains neutral and polar lipids localized in nuclear membranes, nucleoli, nuclear matrix and chromatin. Nuclear lipids may show specific organization forming nuclear lipid microdomains and have both structural and functional roles. Depending on their localization, nuclear lipids play different roles such as the regulation of nuclear membrane and nuclear matrix fluidity but they also can act as platforms for vitamin and hormone function, for active chromatin anchoring, and for the regulation of gene expression, DNA duplication and transcription. Crosstalk among different kinds of lipid signalling pathways influence the physiopathology of numerous cell types. In neural cells the nuclear lipids are involved in cell proliferation, differentiation, inflammation, migration and apoptosis. Abnormal metabolism of nuclear lipids might be closely associated with tumorigenesis and neurodegenerative diseases such as Alzheimer disease and Parkinson disease among others.

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References

  1. Ledeen RW, Wu G (2008) Nuclear sphingolipids: metabolism and signaling. J Lipid Res 49(6):1176–1186. doi:10.1194/jlr.R800009-JLR200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Farooqui AA, Ong WY, Farooqui T (2010) Lipid mediators in the nucleus: their potential contribution to Alzheimer’s disease. Biochim Biophys Acta 1801(8):906–916. doi:10.1016/j.bbalip.2010.02.002

    Article  CAS  PubMed  Google Scholar 

  3. Albi E, Viola Magni MP (2004) The role of intranuclear lipids. Biol Cell 96(8):657–667. doi:10.1016/j.biolcel.2004.05.004

    Article  CAS  PubMed  Google Scholar 

  4. Goto K, Tanaka T, Nakano T, Okada M, Hozumi Y, Topham MK, Martelli AM (2014) DGKzeta under stress conditions: “to be nuclear or cytoplasmic, that is the question”. Adv Biol Regul 54:242–253. doi:10.1016/j.jbior.2013.08.007

    Article  CAS  PubMed  Google Scholar 

  5. Faenza I, Fiume R, Piazzi M, Colantoni A, Cocco L (2013) Nuclear inositide specific phospholipase C signalling: interactions and activity. FEBS J 280(24):6311–6321. doi:10.1111/febs.12450

    Article  CAS  PubMed  Google Scholar 

  6. Garcia del Cano G, Montana M, Aretxabala X, Gonzalez-Burguera I, Lopez de Jesus M, Barrondo S, Salles J (2014) Nuclear phospholipase C-beta1 and diacylglycerol LIPASE-alpha in brain cortical neurons. Adv Biol Regul 54:12–23. doi:10.1016/j.jbior.2013.09.003

    Article  CAS  PubMed  Google Scholar 

  7. Oliveira AG, Guimaraes ES, Andrade LM, Menezes GB, Fatima Leite M (2014) Decoding calcium signaling across the nucleus. Physiol (Bethesda) 29(5):361–368. doi:10.1152/physiol.00056.2013

    CAS  Google Scholar 

  8. Martelli AM, Ognibene A, Buontempo F, Fini M, Bressanin D, Goto K, McCubrey JA, Cocco L, Evangelisti C (2011) Nuclear phosphoinositides and their roles in cell biology and disease. Crit Rev Biochem Mol Biol 46(5):436–457. doi:10.3109/10409238.2011.609530

    Article  CAS  PubMed  Google Scholar 

  9. Kim J, Jahng WJ, Di Vizio D, Lee JS, Jhaveri R, Rubin MA, Shisheva A, Freeman MR (2007) The phosphoinositide kinase PIKfyve mediates epidermal growth factor receptor trafficking to the nucleus. Cancer Res 67(19):9229–9237. doi:10.1158/0008-5472.CAN-07-1333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Garcia del Cano G, Aretxabala X, Gonzalez-Burguera I, Montana M, Lopez de Jesus M, Barrondo S, Barrio RJ, Sampedro C, Goicolea MA, Salles J (2015) Nuclear diacylglycerol lipase-alpha in rat brain cortical neurons: evidence of 2-arachidonoylglycerol production in concert with phospholipase C-beta activity. J Neurochem 132(5):489–503. doi:10.1111/jnc.12963

    CAS  PubMed  Google Scholar 

  11. Raben DM, Tu-Sekine B (2008) Nuclear diacylglycerol kinases: regulation and roles. Front Biosci 13:590–597

    Article  CAS  PubMed  Google Scholar 

  12. Lucki NC, Sewer MB (2012) Nuclear sphingolipid metabolism. Ann Rev Physiol 74:131–151. doi:10.1146/annurev-physiol-020911-153321

    Article  CAS  Google Scholar 

  13. Ledeen RW, Wu G (2015) The multi-tasked life of GM1 ganglioside, a true factotum of nature. Trends Biochem Sci 40(7):407–418. doi:10.1016/j.tibs.2015.04.005

    Article  CAS  PubMed  Google Scholar 

  14. Bartoccini E, Marini F, Damaskopoulou E, Lazzarini R, Cataldi S, Cascianelli G, Gil Garcia M, Albi E (2011) Nuclear lipid microdomains regulate nuclear vitamin D3 uptake and influence embryonic hippocampal cell differentiation. Mol Biol Cell 22(17):3022–3031. doi:10.1091/mbc.E11-03-0196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cascianelli G, Villani M, Tosti M, Marini F, Bartoccini E, Magni MV, Albi E (2008) Lipid microdomains in cell nucleus. Mol Biol Cell 19(12):5289–5295. doi:10.1091/mbc.E08-05-0517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cataldi S, Codini M, Cascianelli G, Tringali S, Tringali AR, Lazzarini A, Floridi A, Bartoccini E, Garcia-Gil M, Lazzarini R, Ambesi-Impiombato FS, Curcio F, Beccari T, Albi E (2014) Nuclear lipid microdomain as resting place of dexamethasone to impair cell proliferation. Int J Mol Sci 11:19832–19846. doi:10.3390/ijms151119832

    Article  CAS  Google Scholar 

  17. Albi E, Lazzarini R, Magni MV (2003) Reverse sphingomyelin-synthase in rat liver chromatin. FEBS Lett 549(1–3):152–156

    Article  CAS  PubMed  Google Scholar 

  18. Ali H, Nakano T, Saino-Saito S, Hozumi Y, Katagiri Y, Kamii H, Sato S, Kayama T, Kondo H, Goto K (2004) Selective translocation of diacylglycerol kinase zeta in hippocampal neurons under transient forebrain ischemia. Neurosci Lett 372(3):190–195. doi:10.1016/j.neulet.2004.09.052

    Article  CAS  PubMed  Google Scholar 

  19. Nakano T, Hozumi Y, Ali H, Saino-Saito S, Kamii H, Sato S, Kayama T, Watanabe M, Kondo H, Goto K (2006) Diacylglycerol kinase zeta is involved in the process of cerebral infarction. Eur J Neurosci 23(6):1427–1435. doi:10.1111/j.1460-9568.2006.04685.x

    Article  PubMed  Google Scholar 

  20. Saino-Saito S, Hozumi Y, Goto K (2011) Excitotoxicity by kainate-induced seizure causes diacylglycerol kinase zeta to shuttle from the nucleus to the cytoplasm in hippocampal neurons. Neurosci Lett 494(3):185–189. doi:10.1016/j.neulet.2011.02.062

    Article  CAS  PubMed  Google Scholar 

  21. Suzuki Y, Yamazaki Y, Hozumi Y, Okada M, Tanaka T, Iseki K, Ohta N, Aoyagi M, Fujii S, Goto K (2012) NMDA receptor-mediated Ca(2+) influx triggers nucleocytoplasmic translocation of diacylglycerol kinase zeta under oxygen-glucose deprivation conditions, an in vitro model of ischemia, in rat hippocampal slices. Histochem Cell Biol 137(4):499–511. doi:10.1007/s00418-011-0907-y

    Article  CAS  PubMed  Google Scholar 

  22. Kiebish MA, Han X, Cheng H, Seyfried TN (2009) In vitro growth environment produces lipidomic and electron transport chain abnormalities in mitochondria from non-tumorigenic astrocytes and brain tumours. ASN Neuro. doi:10.1042/AN20090011

    PubMed  PubMed Central  Google Scholar 

  23. Diaz-Ruiz R, Rigoulet M, Devin A (2011) The Warburg and Crabtree effects: on the origin of cancer cell energy metabolism and of yeast glucose repression. Biochim Biophys Acta 1807(6):568–576. doi:10.1016/j.bbabio.2010.08.010

    Article  CAS  PubMed  Google Scholar 

  24. Beloribi-Djefaflia S, Vasseur S, Guillaumond F (2016) Lipid metabolic reprogramming in cancer cells. Oncogenesis 5:e189. doi:10.1038/oncsis.2015.49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lazzarini A, Macchiarulo A, Floridi A, Coletti A, Cataldi S, Codini M, Lazzarini R, Bartoccini E, Cascianelli G, Ambesi-Impiombato FS, Beccari T, Curcio F, Albi E (2015) Very long chain fatty acid sphingomyelin in nuclear lipid microdomains of hepatocytes and hepatoma cells: can the exchange from C24:0 to C16:0 affect signal proteins and vitamin D receptor?. Mol Biol Cell 26(13):2418–2425 doi:10.1091/mbc.E15-02-0071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bahk YY, Song H, Baek SH, Park BY, Kim H, Ryu SH, Suh PG (1998) Localization of two forms of phospholipase C-beta1, a and b, in C6Bu-1 cells. Biochim Biophysica Acta 1389(1):76–80

    Article  CAS  Google Scholar 

  27. Montana M, Garcia del Cano G, Lopez de Jesus M, Gonzalez-Burguera I, Echeazarra L, Barrondo S, Salles J (2012) Cellular neurochemical characterization and subcellular localization of phospholipase C beta1 in rat brain. Neuroscience 222:239–268. doi:10.1016/j.neuroscience.2012.06.039

    Article  CAS  PubMed  Google Scholar 

  28. Guo Y, Rosati B, Scarlata S (2012) alpha-Synuclein increases the cellular level of phospholipase Cbeta1. Cell Signal 24(5):1109–1114. doi:10.1016/j.cellsig.2012.01.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Guo Y, Scarlata S (2013) A loss in cellular protein partners promotes alpha-synuclein aggregation in cells resulting from oxidative stress. BioChemistry 52(22):3913–3920. doi:10.1021/bi4002425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kontopoulos E, Parvin JD, Feany MB (2006) Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum Mol Genet 15(20):3012–3023. doi:10.1093/hmg/ddl243

    Article  CAS  PubMed  Google Scholar 

  31. Vasudevaraju P, Guerrero E, Hegde ML, Collen TB, Britton GB, Rao KS (2012) New evidence on alpha-synuclein and Tau binding to conformation and sequence specific GC* rich DNA: relevance to neurological disorders. J Pharm Bioallied Sci 4(2):112–117. doi:10.4103/0975-7406.94811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lin WL, DeLucia MW, Dickson DW (2004) Alpha-synuclein immunoreactivity in neuronal nuclear inclusions and neurites in multiple system atrophy. Neurosci Lett 354(2):99–102

    Article  CAS  PubMed  Google Scholar 

  33. Yoshida M (2007) Multiple system atrophy: alpha-synuclein and neuronal degeneration. Neuropathology 27(5):484–493

    Article  PubMed  Google Scholar 

  34. Fares MB, Ait-Bouziad N, Dikiy I, Mbefo MK, Jovicic A, Kiely A, Holton JL, Lee SJ, Gitler AD, Eliezer D, Lashuel HA (2014) The novel Parkinson’s disease linked mutation G51D attenuates in vitro aggregation and membrane binding of alpha-synuclein, and enhances its secretion and nuclear localization in cells. Hum Mol Genet 23(17):4491–4509. doi:10.1093/hmg/ddu165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Koh HY, Kim D, Lee J, Lee S, Shin HS (2008) Deficits in social behavior and sensorimotor gating in mice lacking phospholipase Cbeta1. Genes Brain Behav 7(1):120–128. doi:10.1111/j.1601-183X.2007.00351.x

    PubMed  Google Scholar 

  36. Manning EE, Ransome MI, Burrows EL, Hannan AJ (2012) Increased adult hippocampal neurogenesis and abnormal migration of adult-born granule neurons is associated with hippocampal-specific cognitive deficits in phospholipase C-beta1 knockout mice. Hippocampus 22(2):309–319. doi:10.1002/hipo.20900

    Article  PubMed  Google Scholar 

  37. Koh HY (2013) Phospholipase C-beta1 and schizophrenia-related behaviors. Adv Biol Regul 53(3):242–248. doi:10.1016/j.jbior.2013.08.002

    Article  CAS  PubMed  Google Scholar 

  38. Lo Vasco VR, Cardinale G, Polonia P (2012) Deletion of PLCB1 gene in schizophrenia-affected patients. J Cell Mol Med 16(4):844–851. doi:10.1111/j.1582-4934.2011.01363.x

    Article  PubMed  CAS  Google Scholar 

  39. Udawela M, Scarr E, Hannan AJ, Thomas EA, Dean B (2011) Phospholipase C beta 1 expression in the dorsolateral prefrontal cortex from patients with schizophrenia at different stages of illness. Aust N Z J Psychiatry 45(2):140–147. doi:10.3109/00048674.2010.533364

    Article  PubMed  Google Scholar 

  40. Kurian MA, Meyer E, Vassallo G, Morgan NV, Prakash N, Pasha S, Hai NA, Shuib S, Rahman F, Wassmer E, Cross JH, O’Callaghan FJ, Osborne JP, Scheffer IE, Gissen P, Maher ER (2010) Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy. Brain 133(10):2964–2970. doi:10.1093/brain/awq238

    Article  PubMed  Google Scholar 

  41. Ye K, Snyder SH (2004) PIKE GTPase: a novel mediator of phosphoinositide signaling. J Cell Sci 117(Pt 2):155–161. doi:10.1242/jcs.00924

    Article  CAS  PubMed  Google Scholar 

  42. Okada M, Taguchi K, Maekawa S, Fukami K, Yagisawa H (2010) Calcium fluxes cause nuclear shrinkage and the translocation of phospholipase C-delta1 into the nucleus. Neurosci Lett 472(3):188–193. doi:10.1016/j.neulet.2010.01.081

    Article  CAS  PubMed  Google Scholar 

  43. Choi S, Thapa N, Tan X, Hedman AC, Anderson RA (2015) PIP kinases define PI4,5P(2) signaling specificity by association with effectors. Biochim Biophys Acta 1851(6):711–723. doi:10.1016/j.bbalip.2015.01.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J (2016) Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 73(17):3221–3247. doi:10.1007/s00018-016-2223-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Blind RD (2014) Disentangling biological signaling networks by dynamic coupling of signaling lipids to modifying enzymes. Adv Biol Regul 54:25–38. doi:10.1016/j.jbior.2013.09.015

    Article  CAS  PubMed  Google Scholar 

  46. Reddy DS (2010) Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog Brain Res 186:113–137. doi:10.1016/B978-0-444-53630-3.00008-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Martelli AM, Tabellini G, Bressanin D, Ognibene A, Goto K, Cocco L, Evangelisti C (2012) The emerging multiple roles of nuclear Akt. Biochim Biophysica Acta 1823(12):2168–2178. doi:10.1016/j.bbamcr.2012.08.017

    Article  CAS  Google Scholar 

  48. Davis WJ, Lehmann PZ, Li W (2015) Nuclear PI3K signaling in cell growth and tumorigenesis. Front Cell Dev Biol 3:24. doi:10.3389/fcell.2015.00024

    Article  PubMed  PubMed Central  Google Scholar 

  49. Ahn JY, Rong R, Liu X, Ye K (2004) PIKE/nuclear PI 3-kinase signaling mediates the antiapoptotic actions of NGF in the nucleus. EMBO J 23(20):3995–4006. doi:10.1038/sj.emboj.7600392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kwon IS, Lee KH, Choi JW, Ahn JY (2010) PI(3,4,5)P3 regulates the interaction between Akt and B23 in the nucleus. BMB Rep 43(2):127–132

    Article  CAS  PubMed  Google Scholar 

  51. Lee SB, Xuan Nguyen TL, Choi JW, Lee KH, Cho SW, Liu Z, Ye K, Bae SS, Ahn JY (2008) Nuclear Akt interacts with B23/NPM and protects it from proteolytic cleavage, enhancing cell survival. Proc Natl Acad Sci USA 105(43):16584–16589. doi:10.1073/pnas.0807668105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ahn JY (2014) Neuroprotection signaling of nuclear akt in neuronal cells. Exp Neurobiol 23(3):200–206. doi:10.5607/en.2014.23.3.200

    Article  PubMed  PubMed Central  Google Scholar 

  53. Lee SB, Kwon IS, Park J, Lee KH, Ahn Y, Lee C, Kim J, Choi SY, Cho SW, Ahn JY (2010) Ribosomal protein S3, a new substrate of Akt, serves as a signal mediator between neuronal apoptosis and DNA repair. J Biol Chem 285(38):29457–29468. doi:10.1074/jbc.M110.131367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Elong Edimo W, Derua R, Janssens V, Nakamura T, Vanderwinden JM, Waelkens E, Erneux C (2011) Evidence of SHIP2 Ser132 phosphorylation, its nuclear localization and stability. Biochem J 439(3):391–401. doi:10.1042/BJ20110173

    Article  PubMed  CAS  Google Scholar 

  55. Elong Edimo W, Schurmans S, Roger PP, Erneux C (2014) SHIP2 signaling in normal and pathological situations: its impact on cell proliferation. Adv Biol Regul 54:142–151. doi:10.1016/j.jbior.2013.09.002

    Article  CAS  PubMed  Google Scholar 

  56. Zhang S, Taghibiglou C, Girling K, Dong Z, Lin SZ, Lee W, Shyu WC, Wang YT (2013) Critical role of increased PTEN nuclear translocation in excitotoxic and ischemic neuronal injuries. J Neurosci 33(18):7997–8008. doi:10.1523/JNEUROSCI.5661-12.2013

    Article  CAS  PubMed  Google Scholar 

  57. Albi E, Cataldi S, Bartoccini E, Magni MV, Marini F, Mazzoni F, Rainaldi G, Evangelista M, Garcia-Gil M (2006) Nuclear sphingomyelin pathway in serum deprivation-induced apoptosis of embryonic hippocampal cells. J Cell Physiol 206(1):189–195. doi:10.1002/jcp.20448

    Article  CAS  PubMed  Google Scholar 

  58. Brann AB, Scott R, Neuberger Y, Abulafia D, Boldin S, Fainzilber M, Futerman AH (1999) Ceramide signaling downstream of the p75 neurotrophin receptor mediates the effects of nerve growth factor on outgrowth of cultured hippocampal neurons. J Neurosci 19(19):8199–8206

    CAS  PubMed  Google Scholar 

  59. Watanabe M, Kitano T, Kondo T, Yabu T, Taguchi Y, Tashima M, Umehara H, Domae N, Uchiyama T, Okazaki T (2004) Increase of nuclear ceramide through caspase-3-dependent regulation of the “sphingomyelin cycle” in Fas-induced apoptosis. Cancer Res 64(3):1000–1007

    Article  CAS  PubMed  Google Scholar 

  60. Tsugane K, Tamiya-Koizumi K, Nagino M, Nimura Y, Yoshida S (1999) A possible role of nuclear ceramide and sphingosine in hepatocyte apoptosis in rat liver. J Hepatol 31(1):8–17

    Article  CAS  PubMed  Google Scholar 

  61. Albi E, Magni MP (1997) Chromatin neutral sphingomyelinase and its role in hepatic regeneration. Biochem Biophys Res Commun 236(1):29–33. doi:10.1006/bbrc.1997.6803

    Article  CAS  PubMed  Google Scholar 

  62. Albi E, Pieroni S, Viola Magni MP, Sartori C (2003) Chromatin sphingomyelin changes in cell proliferation and/or apoptosis induced by ciprofibrate. J Cell Physiol 196(2):354–361. doi:10.1002/jcp.10314

    Article  CAS  PubMed  Google Scholar 

  63. Albi E, Magni MV (1999) Sphingomyelin synthase in rat liver nuclear membrane and chromatin. FEBS Lett 460(2):369–372

    Article  CAS  PubMed  Google Scholar 

  64. Rossi G, Magni MV, Albi E (2007) Sphingomyelin-cholesterol and double stranded RNA relationship in the intranuclear complex. Arch Biochem Biophys 459(1):27–32. doi:10.1016/j.abb.2006.11.020

    Article  CAS  PubMed  Google Scholar 

  65. Colombaioni L, Frago LM, Varela-Nieto I, Pesi R, Garcia-Gil M (2002) Serum deprivation increases ceramide levels and induces apoptosis in undifferentiated HN9.10e cells. Neurochem Int 40(4):327–336

    Article  CAS  PubMed  Google Scholar 

  66. Colombaioni L, Colombini L, Garcia-Gil M (2002) Role of mitochondria in serum withdrawal-induced apoptosis of immortalized neuronal precursors. Brain Res Dev Brain Res 134(1–2):93–102

    Article  CAS  PubMed  Google Scholar 

  67. Faustino RS, Cheung P, Richard MN, Dibrov E, Kneesch AL, Deniset JF, Chahine MN, Lee K, Blackwood D, Pierce GN (2008) Ceramide regulation of nuclear protein import. J Lipid Res 49(3):654–662. doi:10.1194/jlr.M700464-JLR200

    Article  CAS  PubMed  Google Scholar 

  68. Farooqui AA (2012) Lipid mediators and their metabolism in the nucleous: implications for Alzheimer’s disease. J Alzheimers Dis 30(Suppl 2):S163–S178. doi:10.3233/JAD-2011-111085

    PubMed  Google Scholar 

  69. Grimm MO, Zimmer VC, Lehmann J, Grimm HS, Hartmann T (2013) The impact of cholesterol, DHA, and sphingolipids on Alzheimer’s disease. Biomed Res Int 2013:814390. doi:10.1155/2013/814390

    Article  PubMed  CAS  Google Scholar 

  70. Marini F, Bartoccini E, Cascianelli G, Voccoli V, Baviglia MG, Magni MV, Garcia-Gil M, Albi E (2010) Effect of 1alpha,25-dihydroxyvitamin D3 in embryonic hippocampal cells. Hippocampus 20(6):696–705. doi:10.1002/hipo.20670

    CAS  PubMed  Google Scholar 

  71. Hait NC, Allegood J, Maceyka M, Strub GM, Harikumar KB, Singh SK, Luo C, Marmorstein R, Kordula T, Milstien S, Spiegel S (2009) Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science 325(5945):1254–1257. doi:10.1126/science.1176709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Milstien S, Gude D, Spiegel S (2007) Sphingosine 1-phosphate in neural signalling and function. Acta Paediatr 96(455):40–43. doi:10.1111/j.1651-2227.2007.00206.x

    Article  PubMed  Google Scholar 

  73. Ghasemi R, Dargahi L, Ahmadiani A (2016) Integrated sphingosine-1 phosphate signaling in the central nervous system: from physiological equilibrium to pathological damage. Pharmacol Res 104:156–164. doi:10.1016/j.phrs.2015.11.006

    Article  CAS  PubMed  Google Scholar 

  74. Wang C, Mao J, Redfield S, Mo Y, Lage JM, Zhou X (2014) Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues. Exp Molecular Pathol 97(2):259–265. doi:10.1016/j.yexmp.2014.07.013

    Article  CAS  Google Scholar 

  75. Hait NC, Wise LE, Allegood JC, O’Brien M, Avni D, Reeves TM, Knapp PE, Lu J, Luo C, Miles MF, Milstien S, Lichtman AH, Spiegel S (2014) Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory. Nat Neurosci 17(7):971–980. doi:10.1038/nn.3728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Noda H, Takeuchi H, Mizuno T, Suzumura A (2013) Fingolimod phosphate promotes the neuroprotective effects of microglia. J Neuroimmunol 256(1–2):13–18. doi:10.1016/j.jneuroim.2012.12.005

    Article  CAS  PubMed  Google Scholar 

  77. Takasugi N, Sasaki T, Ebinuma I, Osawa S, Isshiki H, Takeo K, Tomita T, Iwatsubo T (2013) FTY720/fingolimod, a sphingosine analogue, reduces amyloid-beta production in neurons. PloS One 8(5):e64050. doi:10.1371/journal.pone.0064050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Brunkhorst R, Vutukuri R, Pfeilschifter W (2014) Fingolimod for the treatment of neurological diseases-state of play and future perspectives. Front Cell Neurosci 8:283. doi:10.3389/fncel.2014.00283

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Choi JW, Gardell SE, Herr DR, Rivera R, Lee CW, Noguchi K, Teo ST, Yung YC, Lu M, Kennedy G, Chun J (2011) FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci USA 108(2):751–756. doi:10.1073/pnas.1014154108

    Article  CAS  PubMed  Google Scholar 

  80. di Nuzzo L, Orlando R, Tognoli C, Di Pietro P, Bertini G, Miele J, Bucci D, Motolese M, Scaccianoce S, Caruso A, Mauro G, De Lucia C, Battaglia G, Bruno V, Fabene PF, Nicoletti F (2015) Antidepressant activity of fingolimod in mice. Pharmacol Res Perspect 3(3):e00135. doi:10.1002/prp2.135

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Asle-Rousta M, Kolahdooz Z, Oryan S, Ahmadiani A, Dargahi L (2013) FTY720 (fingolimod) attenuates beta-amyloid peptide (Abeta42)-induced impairment of spatial learning and memory in rats. J Mol Neurosci 50(3):524–532. doi:10.1007/s12031-013-9979-6

    Article  CAS  PubMed  Google Scholar 

  82. Hemmati F, Dargahi L, Nasoohi S, Omidbakhsh R, Mohamed Z, Chik Z, Naidu M, Ahmadiani A (2013) Neurorestorative effect of FTY720 in a rat model of Alzheimer’s disease: comparison with memantine. Behav Brain Res 252:415–421. doi:10.1016/j.bbr.2013.06.016

    Article  CAS  PubMed  Google Scholar 

  83. Rovina P, Schanzer A, Graf C, Mechtcheriakova D, Jaritz M, Bornancin F (2009) Subcellular localization of ceramide kinase and ceramide kinase-like protein requires interplay of their Pleckstrin Homology domain-containing N-terminal regions together with C-terminal domains. Biochim Biophysica Acta 1791(10):1023–1030. doi:10.1016/j.bbalip.2009.05.009

    Article  CAS  Google Scholar 

  84. Lamour NF, Subramanian P, Wijesinghe DS, Stahelin RV, Bonventre JV, Chalfant CE (2009) Ceramide 1-phosphate is required for the translocation of group IVA cytosolic phospholipase A2 and prostaglandin synthesis. J Biol Chem 284(39):26897–26907. doi:10.1074/jbc.M109.001677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Bell E, Ponthan F, Whitworth C, Westermann F, Thomas H, Redfern CP (2013) Cell survival signalling through PPARdelta and arachidonic acid metabolites in neuroblastoma. PloS One 8(7):e68859. doi:10.1371/journal.pone.0068859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Murakami M, Ito H, Hagiwara K, Yoshida K, Sobue S, Ichihara M, Takagi A, Kojima T, Tanaka K, Tamiya-Koizumi K, Kyogashima M, Suzuki M, Banno Y, Nozawa Y, Murate T (2010) ATRA inhibits ceramide kinase transcription in a human neuroblastoma cell line, SH-SY5Y cells: the role of COUP-TFI. J Neurochem 112(2):511–520. doi:10.1111/j.1471-4159.2009.06486.x

    Article  CAS  PubMed  Google Scholar 

  87. Bini F, Frati A, Garcia-Gil M, Battistini C, Granado M, Martinesi M, Mainardi M, Vannini E, Luzzati F, Caleo M, Peretto P, Gomez-Munoz A, Meacci E (2012) New signalling pathway involved in the anti-proliferative action of vitamin D(3) and its analogues in human neuroblastoma cells. A role for ceramide kinase. Neuropharmacology 63(4):524–537. doi:10.1016/j.neuropharm.2012.04.026

    Article  CAS  PubMed  Google Scholar 

  88. Schengrund CL (2015) Gangliosides: glycosphingolipids essential for normal neural development and function. Trends Biochem Sci 40(7):397–406. doi:10.1016/j.tibs.2015.03.007

    Article  CAS  PubMed  Google Scholar 

  89. Copani A, Melchiorri D, Caricasole A, Martini F, Sale P, Carnevale R, Gradini R, Sortino MA, Lenti L, De Maria R, Nicoletti F (2002) Beta-amyloid-induced synthesis of the ganglioside GD3 is a requisite for cell cycle reactivation and apoptosis in neurons. J Neurosci 22(10):3963–3968

    CAS  PubMed  Google Scholar 

  90. Tempera I, Buchetti B, Lococo E, Gradini R, Mastronardi A, Mascellino MT, Sale P, Mosca L, d’Erme M, Lenti L (2008) GD3 nuclear localization after apoptosis induction in HUT-78 cells. Biochem Biophys Res Commun 368(3):495–500. doi:10.1016/j.bbrc.2007.12.196

    Article  CAS  PubMed  Google Scholar 

  91. Garofalo T, Tinari A, Matarrese P, Giammarioli AM, Manganelli V, Ciarlo L, Misasi R, Sorice M, Malorni W (2007) Do mitochondria act as “cargo boats” in the journey of GD3 to the nucleus during apoptosis? FEBS Lett 581(21):3899–3903. doi:10.1016/j.febslet.2007.07.020

    Article  CAS  PubMed  Google Scholar 

  92. Maglione V, Marchi P, Di Pardo A, Lingrell S, Horkey M, Tidmarsh E, Sipione S (2010) Impaired ganglioside metabolism in Huntington’s disease and neuroprotective role of GM1. J Neurosci 30(11):4072–4080. doi:10.1523/JNEUROSCI.6348-09.2010

    Article  CAS  PubMed  Google Scholar 

  93. Xu D, Yang L, Li Y, Sun Y (2015) Clinical study of ganglioside (GM) combined with methylprednisolone (MP) for early acute spinal injury. Pak J Pharm Sci 28(2 Suppl):701–704

    CAS  PubMed  Google Scholar 

  94. Di Pardo A, Maglione V, Alpaugh M, Horkey M, Atwal RS, Sassone J, Ciammola A, Steffan JS, Fouad K, Truant R, Sipione S (2012) Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice. Proc Natl Acad Sci USA 109(9):3528–3533. doi:10.1073/pnas.1114502109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Desplats PA, Denny CA, Kass KE, Gilmartin T, Head SR, Sutcliffe JG, Seyfried TN, Thomas EA (2007) Glycolipid and ganglioside metabolism imbalances in Huntington’s disease. Neurobiol Dis 27(3):265–277. doi:10.1016/j.nbd.2007.05.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Denny CA, Desplats PA, Thomas EA, Seyfried TN (2010) Cerebellar lipid differences between R6/1 transgenic mice and humans with Huntington’s disease. J Neurochem 115(3):748–758. doi:10.1111/j.1471-4159.2010.06964.x

    Article  CAS  PubMed  Google Scholar 

  97. Korem N, Zer-Aviv TM, Ganon-Elazar E, Abush H, Akirav I (2015) Targeting the endocannabinoid system to treat anxiety-related disorders. J Basic Clin Physiol Pharmacol 27(3):193–202. doi:10.1515/jbcpp-2015-0058

    Google Scholar 

  98. Mazier W, Saucisse N, Gatta-Cherifi B, Cota D (2015) The endocannabinoid system: pivotal orchestrator of obesity and metabolic disease. Trends Endocrinol Metab 26(10):524–537. doi:10.1016/j.tem.2015.07.007

    Article  CAS  PubMed  Google Scholar 

  99. Sidhpura N, Parsons LH (2011) Endocannabinoid-mediated synaptic plasticity and addiction-related behavior. Neuropharmacology 61(7):1070–1087. doi:10.1016/j.neuropharm.2011.05.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Smaga I, Bystrowska B, Gawlinski D, Przegalinski E, Filip M (2014) The endocannabinoid/endovanilloid system and depression. Curr Neuropharmacol 12(5):462–474. doi:10.2174/1570159X12666140923205412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Cabral GA, Rogers TJ, Lichtman AH (2015) Turning over a new leaf: cannabinoid and endocannabinoid modulation of immune function. J Neuroimmune Pharmacol 10(2):193–203. doi:10.1007/s11481-015-9615-z

    Article  PubMed  PubMed Central  Google Scholar 

  102. Velasco G, Sanchez C, Guzman M (2015) Endocannabinoids and cancer. Handb Exp Pharmacol 231:449–472. doi:10.1007/978-3-319-20825-1_16

    Article  PubMed  Google Scholar 

  103. Anand P, Whiteside G, Fowler CJ, Hohmann AG (2009) Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain Res Rev 60(1):255–266. doi:10.1016/j.brainresrev.2008.12.003

    Article  CAS  PubMed  Google Scholar 

  104. McIntosh HH, Song C, Howlett AC (1998) CB1 cannabinoid receptor: cellular regulation and distribution in N18TG2 neuroblastoma cells. Brain Res Mol Brain Res 53(1–2):163–173

    Article  CAS  PubMed  Google Scholar 

  105. Busquets Garcia A, Soria-Gomez E, Bellocchio L, Marsicano G (2016) Cannabinoid receptor type-1: breaking the dogmas. F1000 Res. doi:10.12688/f1000research.8245.1

    Google Scholar 

  106. Xu Z, Lv XA, Dai Q, Ge YQ, Xu J (2016) Acute upregulation of neuronal mitochondrial type-1 cannabinoid receptor and it’s role in metabolic defects and neuronal apoptosis after TBI. Mol Brain 9(1):75. doi:10.1186/s13041-016-0257-8

    Article  PubMed  PubMed Central  Google Scholar 

  107. Fernandez-Ruiz J, Romero J, Ramos JA (2015) Endocannabinoids and neurodegenerative disorders: Parkinson’s disease, Huntington’s chorea, Alzheimer’s disease, and others. Handb Exp Pharmacol 231:233–259. doi:10.1007/978-3-319-20825-1_8

    Article  PubMed  Google Scholar 

  108. Galve-Roperh I, Chiurchiu V, Diaz-Alonso J, Bari M, Guzman M, Maccarrone M (2013) Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation. Prog Lipid Res 52(4):633–650. doi:10.1016/j.plipres.2013.05.004

    Article  CAS  PubMed  Google Scholar 

  109. Albi E, Peloso I, Magni MV (1999) Nuclear membrane sphingomyelin-cholesterol changes in rat liver after hepatectomy. Biochem Biophys Res Commun 262(3):692–695. doi:10.1006/bbrc.1999.1188

    Article  CAS  PubMed  Google Scholar 

  110. Albi E, Magni MV (2002) The presence and the role of chromatin cholesterol in rat liver regeneration. J Hepatol 36(3):395–400

    Article  CAS  PubMed  Google Scholar 

  111. Albi E, Cataldi S, Rossi G, Magni MV (2003) A possible role of cholesterol-sphingomyelin/phosphatidylcholine in nuclear matrix during rat liver regeneration. J Hepatol 38(5):623–628

    Article  CAS  PubMed  Google Scholar 

  112. Gamba P, Testa G, Gargiulo S, Staurenghi E, Poli G, Leonarduzzi G (2015) Oxidized cholesterol as the driving force behind the development of Alzheimer’s disease. Front Aging Neurosci 7:119. doi:10.3389/fnagi.2015.00119

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Leoni V, Caccia C (2015) The impairment of cholesterol metabolism in Huntington disease. Biochim Biophys Acta 1851(8):1095–1105. doi:10.1016/j.bbalip.2014.12.018

    Article  CAS  PubMed  Google Scholar 

  114. Martin MG, Pfrieger F, Dotti CG (2014) Cholesterol in brain disease: sometimes determinant and frequently implicated. EMBO Rep 15(10):1036–1052. doi:10.15252/embr.201439225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Sacchetti P, Sousa KM, Hall AC, Liste I, Steffensen KR, Theofilopoulos S, Parish CL, Hazenberg C, Richter LA, Hovatta O, Gustafsson JA, Arenas E (2009) Liver X receptors and oxysterols promote ventral midbrain neurogenesis in vivo and in human embryonic stem cells. Cell Stem Cell 5(4):409–419. doi:10.1016/j.stem.2009.08.019

    Article  CAS  PubMed  Google Scholar 

  116. Theofilopoulos S, Wang Y, Kitambi SS, Sacchetti P, Sousa KM, Bodin K, Kirk J, Salto C, Gustafsson M, Toledo EM, Karu K, Gustafsson JA, Steffensen KR, Ernfors P, Sjovall J, Griffiths WJ, Arenas E (2013) Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis. Nat Chem Biol 9(2):126–133. doi:10.1038/nchembio.1156

    Article  CAS  PubMed  Google Scholar 

  117. Andersson S, Gustafsson N, Warner M, Gustafsson JA (2005) Inactivation of liver X receptor beta leads to adult-onset motor neuron degeneration in male mice. Proc Natl Acad Sci USA 102(10):3857–3862. doi:10.1073/pnas.0500634102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Courtney R, Landreth GE (2016) LXR Regulation of brain cholesterol: from development to disease. Trends Endocrinol Metab 27(6):404–414. doi:10.1016/j.tem.2016.03.018

    Article  CAS  PubMed  Google Scholar 

  119. Kiebish MA, Han X, Cheng H, Chuang JH, Seyfried TN (2008) Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: lipidomic evidence supporting the Warburg theory of cancer. J Lipid Res 49(12):2545–2556. doi:10.1194/jlr.M800319-JLR200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by local grants from University of Pisa. The funding agency had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. Department of Biology, University of Pisa, via S. Zeno 31, 56127, Pisa, Italy

    Mercedes Garcia-Gil

  2. Interdepartmental Research Center “Nutraceuticals and Food for Health”, University of Pisa, Pisa, Italy

    Mercedes Garcia-Gil

  3. Laboratory of Nuclear Lipid BioPathology, CRABiON, Perugia, Italy

    Elisabetta Albi

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  1. Mercedes Garcia-Gil
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Correspondence to Mercedes Garcia-Gil.

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Garcia-Gil, M., Albi, E. Nuclear Lipids in the Nervous System: What they do in Health and Disease. Neurochem Res 42, 321–336 (2017). https://doi.org/10.1007/s11064-016-2085-8

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