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Molecular profile and peripheral markers of neurodegeneration in patients with Niemann-Pick type C: Decrease in Plasminogen Activator Inhibitor type 1 and Platelet-Derived Growth Factor type AA

2023-02Journal article Restricted access
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dc.contributor.authorHammerschmidt, Tatiane Grazieli
dc.contributor.authorEncarnação, Marisa
dc.contributor.authorLamberty Faverzani, Jéssica
dc.contributor.authorde Fátima Lopes, Franciele
dc.contributor.authorOliveira, Fabiano Poswar de
dc.contributor.authorFischinger Moura de Sousa, Carolina
dc.contributor.authorRibeiro, Isaura
dc.contributor.authorAlves, Sandra
dc.contributor.authorGiugliani, Roberto
dc.contributor.authorRegla Vargas, Carmen
dc.date.accessioned2024-01-17T10:54:42Z
dc.date.available2024-01-17T10:54:42Z
dc.date.issued2023-02
dc.description.abstractNiemann-Pick type C1 (NPC1) is a fatal inherited disease, caused by pathogenic variants in NPC1 gene, which leads to intracellular accumulation of non-esterified cholesterol and glycosphingolipids. This accumulation leads to a wide range of clinical manifestations, including neurological and cognitive impairment as well as psychiatric disorders. The pathophysiology of cerebral damage involves loss of Purkinje cells, synaptic disturbance, and demyelination. Miglustat, a reversible inhibitor of glucosylceramide synthase, is an approved treatment for NPC1 and can slow neurological damage. The aim of this study was to assess the levels of peripheric neurodegeneration biomarkers of NPC1 patients, namely brain-derived neurotrophic factor (BDNF), platelet-derived growth factors (PDGF-AA and PDGF-AB/BB), neural cell adhesion molecule (NCAM), PAI-1 Total and Cathepsin-D, as well as the levels of cholestane-3β,5α,6β-triol (3β,5α,6β-triol), a biomarker for NPC1. Molecular analysis of the NPC1 patients under study was performed by next generation sequencing (NGS) in cultured fibroblasts. We observed that NPC1 patients treated with miglustat have a significant decrease in PAI-1 total and PDGF-AA concentrations, and no alteration in BDNF, NCAM, PDGF-AB/BB and Cathepsin D. We also found that NPC1 patients treated with miglustat have normalized levels of 3β,5α,6β-triol. The molecular analysis showed four described mutations, and for two patients was not possible to identify the second mutated allele. Our results indicate that the decrease of PAI-1 and PDGF-AA in NPC1 patients could be involved in the pathophysiology of this disease. This is the first work to analyze those plasmatic markers of neurodegenerative processes in NPC1 patients.pt_PT
dc.description.abstractHighlights: Niemann-Pick type C 1 is a fatal inherited rare disease, caused by mutations in NPC1 gene; Neurodegeneration is a feature in this disease and the treatment with miglustat can mitigate it; We found that miglustat can decrease levels of PDGF-AA and PAI-1; These biomarkers might be useful to follow up the disease progression in NPC1.pt_PT
dc.description.sponsorshipThis work was supported by: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/MEC-Brasil); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/MCTI-Brasil number 430443/2018-8); Fundo de Incentivo à Pesquisa e Eventos (FIPE/HCPA Brasil - number 2018-0648.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationArch Biochem Biophys. 2023 Feb:735:109510. doi: 10.1016/j.abb.2023.109510. Epub 2023 Jan 4.pt_PT
dc.identifier.doi10.1016/j.abb.2023.109510pt_PT
dc.identifier.issn0003-9861
dc.identifier.urihttp://hdl.handle.net/10400.18/8912
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/pii/S0003986123000097?via%3Dihubpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectLysosomal Storage Diseasespt_PT
dc.subjectNiemann-Pick type Cpt_PT
dc.subjectMiglustatpt_PT
dc.subjectNeurodegenerationpt_PT
dc.subjectNext Generation Sequencingpt_PT
dc.subjectInherited Diseasept_PT
dc.subjectRare Diseasept_PT
dc.subjectDoenças Lisossomais de Sobrecargapt_PT
dc.subjectNiemann Pick tipo Cpt_PT
dc.subjectGenética Humanapt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleMolecular profile and peripheral markers of neurodegeneration in patients with Niemann-Pick type C: Decrease in Plasminogen Activator Inhibitor type 1 and Platelet-Derived Growth Factor type AApt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.startPage109510pt_PT
oaire.citation.titleArchives of Biochemistry and Biophysicspt_PT
oaire.citation.volume735pt_PT
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT

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