{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T23:50:33Z","timestamp":1780098633918,"version":"3.54.0"},"reference-count":41,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2016,3,11]],"date-time":"2016-03-11T00:00:00Z","timestamp":1457654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Deregulation of the cholesterol pathway is an anomaly observed in human diseases, many of which have in common neurological involvement and unknown pathogenesis. In this study we have used Mevalonate Kinase Deficiency (MKD) as a disease-model in order to investigate the link between the deregulation of the mevalonate pathway and the consequent neurodegeneration. The blocking of the mevalonate pathway in a neuronal cell line (Daoy), using statins or mevalonate, induced an increase in the expression of the inflammasome gene (NLRP3) and programmed cell death related to mitochondrial dysfunction. The morphology of the mitochondria changed, clearly showing the damage induced by oxidative stress and the decreased membrane potential associated with the alterations of the mitochondrial function. The co-administration of geranylgeraniol (GGOH) reduced the inflammatory marker and the damage of the mitochondria, maintaining its shape and components. Our data allow us to speculate about the mechanism by which isoprenoids are able to rescue the inflammatory marker in neuronal cells, independently from the block of the mevalonate pathway, and about the fact that cell death is mitochondria-related.<\/jats:p>","DOI":"10.3390\/ijms17030365","type":"journal-article","created":{"date-parts":[[2016,3,14]],"date-time":"2016-03-14T11:03:45Z","timestamp":1457953425000},"page":"365","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Geranylgeraniol and Neurological Impairment: Involvement of Apoptosis and Mitochondrial Morphology"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3427-618X","authenticated-orcid":false,"given":"Annalisa","family":"Marcuzzi","sequence":"first","affiliation":[{"name":"Piazzale Europa 1, University of Trieste, Trieste 34127, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7374-1684","authenticated-orcid":false,"given":"Elisa","family":"Piscianz","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health\u2014IRCCS \u201cBurlo Garofolo\u201d, Via dell\u2019Istria, 65\/1, Trieste 34137, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Zweyer","sequence":"additional","affiliation":[{"name":"Piazzale Europa 1, University of Trieste, Trieste 34127, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Bortul","sequence":"additional","affiliation":[{"name":"Piazzale Europa 1, University of Trieste, Trieste 34127, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1096-042X","authenticated-orcid":false,"given":"Claudia","family":"Loganes","sequence":"additional","affiliation":[{"name":"Piazzale Europa 1, University of Trieste, Trieste 34127, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Girardelli","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health\u2014IRCCS \u201cBurlo Garofolo\u201d, Via dell\u2019Istria, 65\/1, Trieste 34137, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2625-9454","authenticated-orcid":false,"given":"Gabriele","family":"Baj","sequence":"additional","affiliation":[{"name":"Piazzale Europa 1, University of Trieste, Trieste 34127, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7774-548X","authenticated-orcid":false,"given":"Lorenzo","family":"Monasta","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health\u2014IRCCS \u201cBurlo Garofolo\u201d, Via dell\u2019Istria, 65\/1, Trieste 34137, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Celeghini","sequence":"additional","affiliation":[{"name":"Piazzale Europa 1, University of Trieste, Trieste 34127, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2016,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.cell.2015.01.036","article-title":"A century of cholesterol and coronaries: From plaques to genes to statins","volume":"161","author":"Goldstein","year":"2015","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1146\/annurev.genet.41.110306.130315","article-title":"Regulation of sterol synthesis in eukaryotes","volume":"41","author":"Espenshade","year":"2007","journal-title":"Annu. Rev. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.jsbmb.2005.08.004","article-title":"Enzymes involved in the formation and transformation of steroid hormones in the fetal and placental compartments","volume":"97","author":"Pasqualini","year":"2005","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"184","DOI":"10.4254\/wjh.v4.i6.184","article-title":"Regulation and deregulation of cholesterol homeostasis: The liver as a metabolic \u201cpower station\u201d","volume":"4","author":"Trapani","year":"2012","journal-title":"World J. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/s00281-015-0492-6","article-title":"Hyper-IgD syndrome\/mevalonate kinase deficiency: What is new?","volume":"37","author":"Simon","year":"2015","journal-title":"Semin. Immunopathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1159\/000360490","article-title":"Clinical presentations of coenzyme q10 deficiency syndrome","volume":"5","author":"Quinzii","year":"2014","journal-title":"Mol. Syndromol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1146\/annurev-genom-091212-153412","article-title":"Disorders of cholesterol metabolism and their unanticipated convergent mechanisms of disease","volume":"15","author":"Platt","year":"2014","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5746","DOI":"10.2174\/138161212803530835","article-title":"Mevalonate kinase deficiency: Disclosing the role of mevalonate pathway modulation in inflammation","volume":"18","author":"Marcuzzi","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"20607","DOI":"10.3390\/ijms151120607","article-title":"Molecular Mechanisms Underlying the Effects of Statins in the Central Nervous System","volume":"15","author":"McFarland","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2788","DOI":"10.2174\/0929867321666140303142902","article-title":"Cholesterol homeostasis failure in the brain: Implications for synaptic dysfunction and cognitive decline","volume":"21","author":"Segatto","year":"2014","journal-title":"Curr. Med. Chem."},{"key":"ref_11","first-page":"746","article-title":"Dysregulation of cholesterol balance in the brain: Contribution to neurodegenerative diseases","volume":"5","author":"Vance","year":"2012","journal-title":"Dis. Models Mech."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.plipres.2011.06.002","article-title":"Cholesterol metabolism in neurons and astrocytes","volume":"50","author":"Pfrieger","year":"2011","journal-title":"Prog. Lipid Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"23274","DOI":"10.3390\/ijms141223274","article-title":"Mevalonate kinase deficiency and neuroinflammation: Balance between apoptosis and pyroptosis","volume":"14","author":"Tricarico","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.ijdevneu.2012.06.002","article-title":"Lovastatin-induced apoptosis is modulated by geranylgeraniol in a neuroblastoma cell line","volume":"30","author":"Marcuzzi","year":"2012","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e585","DOI":"10.1038\/cddis.2013.112","article-title":"Lovastatin induces apoptosis through the mitochondrial pathway in an undifferentiated SH-SY5Y neuroblastoma cell line","volume":"4","author":"Marcuzzi","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3690","DOI":"10.1002\/art.22194","article-title":"A role for geranylgeranylation in interleukin-1\u03b2 secretion","volume":"54","author":"Mandey","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s10545-010-9173-8","article-title":"Compromized geranylgeranylation of RhoA and Rac1 in mevalonate kinase deficiency","volume":"33","author":"Henneman","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_18","first-page":"260","article-title":"Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: Introducing a vaccination provocation model","volume":"63","author":"Bodar","year":"2005","journal-title":"Neth. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1111\/j.1476-5381.2009.00465.x","article-title":"Geranylgeraniol prevents the cytotoxic effects of mevastatin in THP-1 cells, without decreasing the beneficial effects on cholesterol synthesis","volume":"158","author":"Campia","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6843","DOI":"10.3390\/ijms15046843","article-title":"Block of the mevalonate pathway triggers oxidative and inflammatory molecular mechanisms modulated by exogenous isoprenoid compounds","volume":"15","author":"Kleiner","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3586","DOI":"10.1182\/blood.V85.12.3586.bloodjournal85123586","article-title":"Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome","volume":"85","author":"Drenth","year":"1995","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S137","DOI":"10.1007\/s000110050304","article-title":"Sequential generation of cytokines during the initiative phase of inflammation, with reference to neutrophils","volume":"47","author":"Matsukawa","year":"1998","journal-title":"Inflamm. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.intimp.2010.03.008","article-title":"Natural isoprenoids inhibit LPS-induced-production of cytokines and nitric oxide in aminobisphosphonate-treated monocytes","volume":"10","author":"Marcuzzi","year":"2010","journal-title":"Int. Immunopharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1007\/s00018-003-3018-7","article-title":"Cholesterol homeostasis and function in neurons of the central nervous system","volume":"60","author":"Pfrieger","year":"2003","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1007\/s10495-015-1139-8","article-title":"Microglia activation and interaction with neuronal cells in a biochemical model of mevalonate kinase deficiency","volume":"20","author":"Tricarico","year":"2015","journal-title":"Apoptosis"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s12950-015-0048-5","article-title":"Knockdown of MVK does not lead to changes in NALP3 expression or activation","volume":"12","author":"Celsi","year":"2015","journal-title":"J. Inflamm (Lond)."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3517","DOI":"10.4049\/jimmunol.1202628","article-title":"Gene deletion of Gabarap enhances Nlrp3 inflammasome-dependent inflammatory responses","volume":"190","author":"Zhang","year":"2013","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"15514","DOI":"10.1073\/pnas.1414859111","article-title":"Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy","volume":"111","author":"Yu","year":"2014","journal-title":"PNAS"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1016\/j.bbagen.2013.08.014","article-title":"Ambiguities in NLRP3 inflammasome regulation: Is there a role for mitochondria?","volume":"1840","author":"Lawlor","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2852","DOI":"10.1523\/JNEUROSCI.20-08-02852.2000","article-title":"Geranylgeranyl-pyrophosphate, an isoprenoid of mevalonate cascade, is a critical compound for rat primary cultured cortical neurons to protect the cell death induced by 3-hydroxy-3-methylglutaryl-CoA reductase inhibition","volume":"20","author":"Tanaka","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nature09663","article-title":"A role for mitochondria in NLRP3 inflammasome activation","volume":"469","author":"Zhou","year":"2011","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"613","DOI":"10.4049\/jimmunol.1100613","article-title":"Cutting edge: Reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome","volume":"187","author":"Bauernfeind","year":"2011","journal-title":"J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1089\/ars.2015.6289","article-title":"Mitochondrial redox dysfunction and environmental exposures","volume":"23","author":"Caito","year":"2015","journal-title":"Antioxid. Redox Signal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2741","DOI":"10.1093\/eurheartj\/ehq396","article-title":"Is oxidative stress a therapeutic target in cardiovascular disease?","volume":"31","author":"Gori","year":"2010","journal-title":"Eur. Heart J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1080\/15216540601178091","article-title":"Mitochondrial energy metabolism and redox state in dyslipidemias","volume":"59","author":"Vercesi","year":"2007","journal-title":"IUBMB Life"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1007\/s00784-014-1394-z","article-title":"Isoprenoid geranylgeraniol: The influence on cell characteristics of endothelial progenitor cells after bisphosphonate therapy in vitro","volume":"19","author":"Pabst","year":"2015","journal-title":"Clin. Oral. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1042\/BST20140319","article-title":"The blood-brain barrier endothelium: A target for pro-inflammatory cytokines","volume":"43","author":"Rochfort","year":"2015","journal-title":"Biochem. Soc. Trans."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.neuropharm.2014.10.027","article-title":"Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability","volume":"96","author":"Vezzani","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"315","DOI":"10.3389\/fnins.2014.00315","article-title":"Inflammasomes in neuroinflammation and changes in brain function: A focused review","volume":"8","author":"Singhal","year":"2014","journal-title":"Front. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/gkp045","article-title":"Amplification efficiency: Linking baseline and bias in the analysis of quantitative PCR data","volume":"237","author":"Ruijter","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/3\/365\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:20:32Z","timestamp":1760210432000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/3\/365"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,11]]},"references-count":41,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2016,3]]}},"alternative-id":["ijms17030365"],"URL":"https:\/\/doi.org\/10.3390\/ijms17030365","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,11]]}}}