Browsing by Author "SARAIVA, M.J."
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- Activation of ERK1/2 MAP kinases in familial amyloidotic polyneuropathyPublication . MONTEIRO, F.A.; SOUSA, M.M.; CARDOSO, I.; Barbas-Amaral, J.; GUIMARAES, A.; SARAIVA, M.J.J Neurochem. 2006 Apr;97(1):151-61. Epub 2006 Mar 3. Activation of ERK1/2 MAP kinases in familial amyloidotic polyneuropathy. Monteiro FA, Sousa MM, Cardoso I, do Amaral JB, Guimarães A, Saraiva MJ. Molecular Neurobiology, Instituto de Biologia Celular e Molecular, ICBAS, University of Porto, and Estomatology, Maxillofacial Surgery, Hospital Geral de Santo António, Portugal. Abstract Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disorder characterized by the extracellular deposition of transthyretin (TTR), especially in the PNS. Given the invasiveness of nerve biopsy, salivary glands (SG) from FAP patients were used previously in microarray analysis; mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1) was down-regulated in FAP. Results were validated by RT-PCR and immunohistochemistry both in SG and in nerve biopsies of different stages of disease progression. MKP-3 was also down-regulated in FAP SG biopsies. Given the relationship between MKPs and MAPKs, the latter were investigated. Only extracellular signal-regulated kinases 1/2 (ERK1/2) displayed increased activation in FAP SG and nerves. ERK1/2 kinase (MEK1/2) activation was also up-regulated in FAP nerves. In addition, an FAP transgenic mouse model revealed increased ERK1/2 activation in peripheral nerve affected with TTR deposition when compared to control animals. Cultured rat Schwannoma cell line treatment with TTR aggregates stimulated ERK1/2 activation, which was partially mediated by the receptor for advanced glycation end-products (RAGE). Moreover, caspase-3 activation triggered by TTR aggregates was abrogated by U0126, a MEK1/2 inhibitor, indicating that ERK1/2 activation is essential for TTR aggregates-induced cytotoxicity. Taken together, these data suggest that abnormally sustained activation of ERK in FAP may represent an early signaling cascade leading to neurodegeneration. PMID: 16515552 [PubMed - indexed for MEDLINE]
- Biomarkers in the assessment of therapies for familial amyloidotic polyneuropathyPublication . MACEDO, B.; BATISTA, A.R.; Barbas-Amaral, J.; SARAIVA, M.J.Mol Med. 2007 Nov-Dec;13(11-12):584-91. Biomarkers in the assessment of therapies for familial amyloidotic polyneuropathy. Macedo B, Batista AR, do Amaral JB, Saraiva MJ. SourceMolecular Neurobiology, Instituto de Biologia Molecular e Celular, Porto, Portugal. Abstract The identification of specific biomarkers provides opportunities to develop early diagnostic parameters, monitor disease progression, and test drug efficiency in clinical trials. We previously demonstrated that in familial amyloidotic polyneuropathy (FAP) related to the abnormal extracellular tissue deposition of mutant transthyretin (TTR), inflammatory and apoptotic pathways are triggered in the presymptomatic stages of the disease, when nonfibrillar TTR deposits are present. In the present work, to better define biomarkers for future assessment of prophylactic and therapeutic drugs in the treatment of FAP, we extended the search for oxidative stress and apoptotic biomarkers to clinical samples and animal models presenting nonfibrillar and fibrillar TTR. We found that lipid peroxidation measured by hydroxynonenal, oxidative DNA damage measured by 8-hydroxy-2'-deoxyguanosine, and cellular redox homeostasis measured by glutaredoxin 1 were consistently increased in biopsy specimens from FAP patients and in tissues from transgenic mouse models presenting nonfibrillar TTR deposition. Death-receptor Fas, caspase-8, and Bax were also found to be increased, indicative of the involvement of death receptors in the observed apoptosis process. Removal of TTR deposition by an immunization protocol resulted in significant decreases of the selected markers we describe, corroborating the relationship between TTR deposition, oxidative stress, and apoptosis. Taken together, our results provide a robust biomarker profile for initial experimental animal studies and clinical trials to assess the application of the selected markers in therapies aimed at removal and/or inhibition of TTR polymerization. PMID: 17932549 [PubMed - indexed for MEDLINE] PMCID: PMC2017105Free PMC Article Images from this publication.See all images (5) Free text Figure 1 (A) Top panels: Representative 4-hydroxy-2-nonenal (HNE) staining of salivary glands from healthy individuals (left, n = 6) and FAP patients (right, n = 6). Middle panels: Representative HNE staining in stomach tissue of hTTR Met30 mice without TTR deposition (−/−, left, n = 5) and with TTR deposition (+/−, right, n = 5) ... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Figure 2 Top 2 panels: Representative Grx1 and Trx1 staining of salivary glands from healthy individuals (left, n = 6) and FAP patients (right, n = 6); nuclear staining is indicated by the arrow. Middle panel: Representative Grx1 staining in stomach tissue of hTTR Met30/(+/−)hsf mice without TTR deposition (−/−, left, n = 5) and wi... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Figure 3 Representative FasL, Fas, active caspase-8, active caspase-3, and Bax staining of salivary glands from healthy individuals (left, n = 6) and FAP patients (right, n = 6). 20× magnification. Quantitation of IHC images of FasL, Fas, active caspase-8, active caspase-3, and Bax staining are represented a... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Figure 4 Representative Fas (upper panels) and Bax (bottom panels) staining in stomach and DRG tissue of TTR transgenic mice. Upper panels: Stomach tissue of hTTR Met30 mice without TTR deposition (−/−, left, n = 5) and with TTR deposition (+/−, right, n = 5), of hTTR Met30/(+/−)HSF1-KO, without TTR deposition (−/−, left, n = 6) and with TTR de... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Figure 5 Representative immunohistochemistry of TTR, BiP, Fas, Bax, 8-OHdG and Grx1 in stomach tissue of TTR Y78F immunized transgenic mice 9–10 months old (right; n = 6) and nonimmunized age-matched controls (left; n = 6). 20× magnification; Quantification of IHC images of TTR, BiP, Fas, Bax, 8-OHdG, and Gr... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Publication Types, MeSH Terms, SubstancesPublication Types Research Support, Non-U.S. Gov't MeSH Terms Amyloidosis, Familial/metabolism Amyloidosis, Familial/therapy* Animals Animals, Genetically Modified Apoptosis Biological Markers/metabolism* DNA Damage Immunohistochemistry Mice Oxidative Stress Polyneuropathies/metabolism Polyneuropathies/therapy* Prealbumin/metabolism Substances Biological Markers Prealbumin
- Familial amyloid polyneuropathy associated with TTRSer50Arg mutation in two Iberian families presenting a novel single base change in the mutant genePublication . MUNAR‐QUÉS, M.; MASJUAN, J.; COELHO, T; MOREIRA, P.; VIADER‐FARRÉ, C.; SARAIVA, M.J.Amyloid. 2007 Jun;14(2):147-52. Familial amyloid polyneuropathy associated with TTRSer50Arg mutation in two Iberian families presenting a novel single base change in the mutant gene. Munar-Qués M, Masjuan J, Coelho T, Moreira P, Viader-Farré C, Saraiva MJ. Grupo de Estudio de la PAF, Plaza Olivar 5, 07002 Palma de Mallorca, Majorca, Spain. munar-ques@ogm.jazztel.es Abstract We present two families, from Spain and Portugal, with familial amyloid polyneuropathy (FAP) associated with the mutation TTRSer50Arg. This mutation was first described in two Japanese patients from independent families and later in a French-Italian patient and a Vietnamese family. The two families presented here, are the first to be diagnosed with this mutation in the Iberian Peninsula. In the patients of both families, FAP was very aggressive as they rapidly developed multiple symptoms with progressive deterioration; we emphasize the presence of severe orthostatic hypotension in the Spanish proband which confined him to a wheelchair. This proband was the first patient with this mutation to have undergone liver transplantation and results were encouraging. The mutation was detected in four patients and one disease-free relative by DNA sequencing of exon 3 and induced mutation restriction analysis. The most outstanding feature was the single base transversion A to C in codon 50 (CGT instead of AGT), whereas in both Japanese patients and the French-Italian patient it was T to G (AGG instead of AGT). To our knowledge only six FAP mutations with more than one single nucleotide mutation for the same codon have been reported to date. PMID: 17577688 [PubMed - indexed for MEDLINE]