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1.
Nat Commun ; 15(1): 3490, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664429

RESUMO

Congenital nucleotide excision repair (NER) deficiency gives rise to several cancer-prone and/or progeroid disorders. It is not understood how defects in the same DNA repair pathway cause different disease features and severity. Here, we show that the absence of functional ERCC1-XPF or XPG endonucleases leads to stable and prolonged binding of the transcription/DNA repair factor TFIIH to DNA damage, which correlates with disease severity and induces senescence features in human cells. In vivo, in C. elegans, this prolonged TFIIH binding to non-excised DNA damage causes developmental arrest and neuronal dysfunction, in a manner dependent on transcription-coupled NER. NER factors XPA and TTDA both promote stable TFIIH DNA binding and their depletion therefore suppresses these severe phenotypical consequences. These results identify stalled NER intermediates as pathogenic to cell functionality and organismal development, which can in part explain why mutations in XPF or XPG cause different disease features than mutations in XPA or TTDA.


Assuntos
Caenorhabditis elegans , Dano ao DNA , Reparo do DNA , Proteínas de Ligação a DNA , Endonucleases , Fator de Transcrição TFIIH , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Humanos , Animais , Fator de Transcrição TFIIH/metabolismo , Fator de Transcrição TFIIH/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Endonucleases/metabolismo , Endonucleases/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteína de Xeroderma Pigmentoso Grupo A/metabolismo , Proteína de Xeroderma Pigmentoso Grupo A/genética , Ligação Proteica , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Mutação , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética
2.
NAR Cancer ; 5(4): zcad057, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38058548

RESUMO

The therapeutic efficacy of cisplatin and oxaliplatin depends on the balance between the DNA damage induction and the DNA damage response of tumor cells. Based on clinical evidence, oxaliplatin is administered to cisplatin-unresponsive cancers, but the underlying molecular causes for this tumor specificity are not clear. Hence, stratification of patients based on DNA repair profiling is not sufficiently utilized for treatment selection. Using a combination of genetic, transcriptomics and imaging approaches, we identified factors that promote global genome nucleotide excision repair (GG-NER) of DNA-platinum adducts induced by oxaliplatin, but not by cisplatin. We show that oxaliplatin-DNA lesions are a poor substrate for GG-NER initiating factor XPC and that DDB2 and HMGA2 are required for efficient binding of XPC to oxaliplatin lesions and subsequent GG-NER initiation. Loss of DDB2 and HMGA2 therefore leads to hypersensitivity to oxaliplatin but not to cisplatin. As a result, low DDB2 levels in different colon cancer cells are associated with GG-NER deficiency and oxaliplatin hypersensitivity. Finally, we show that colon cancer patients with low DDB2 levels have a better prognosis after oxaliplatin treatment than patients with high DDB2 expression. We therefore propose that DDB2 is a promising predictive marker of oxaliplatin treatment efficiency in colon cancer.

3.
Nucleic Acids Res ; 51(17): 9055-9074, 2023 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-37470997

RESUMO

The SWI/SNF family of ATP-dependent chromatin remodeling complexes is implicated in multiple DNA damage response mechanisms and frequently mutated in cancer. The BAF, PBAF and ncBAF complexes are three major types of SWI/SNF complexes that are functionally distinguished by their exclusive subunits. Accumulating evidence suggests that double-strand breaks (DSBs) in transcriptionally active DNA are preferentially repaired by a dedicated homologous recombination pathway. We show that different BAF, PBAF and ncBAF subunits promote homologous recombination and are rapidly recruited to DSBs in a transcription-dependent manner. The PBAF and ncBAF complexes promote RNA polymerase II eviction near DNA damage to rapidly initiate transcriptional silencing, while the BAF complex helps to maintain this transcriptional silencing. Furthermore, ARID1A-containing BAF complexes promote RNaseH1 and RAD52 recruitment to facilitate R-loop resolution and DNA repair. Our results highlight how multiple SWI/SNF complexes perform different functions to enable DNA repair in the context of actively transcribed genes.


Assuntos
Proteínas Cromossômicas não Histona , Estruturas R-Loop , Montagem e Desmontagem da Cromatina/genética , Proteínas Cromossômicas não Histona/metabolismo , DNA , Reparo do DNA/genética , Recombinação Homóloga/genética , Humanos
4.
Cell Mol Life Sci ; 79(3): 166, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35230528

RESUMO

The XPG/ERCC5 endonuclease was originally identified as the causative gene for Xeroderma Pigmentosum complementation group G. Ever since its discovery, in depth biochemical, structural and cell biological studies have provided detailed mechanistic insight into its function in excising DNA damage in nucleotide excision repair, together with the ERCC1-XPF endonuclease. In recent years, it has become evident that XPG has additional important roles in genome maintenance that are independent of its function in NER, as XPG has been implicated in protecting replication forks by promoting homologous recombination as well as in resolving R-loops. Here, we provide an overview of the multitasking of XPG in genome maintenance, by describing in detail how its activity in NER is regulated and the evidence that points to important functions outside of NER. Furthermore, we present the various disease phenotypes associated with inherited XPG deficiency and discuss current ideas on how XPG deficiency leads to these different types of disease.


Assuntos
Proteínas de Ligação a DNA/genética , Endonucleases/genética , Genoma/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Animais , Reparo do DNA/genética , Replicação do DNA/genética , Humanos , Xeroderma Pigmentoso/genética
5.
Nat Commun ; 11(1): 4868, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985517

RESUMO

DNA damage sensors DDB2 and XPC initiate global genome nucleotide excision repair (NER) to protect DNA from mutagenesis caused by helix-distorting lesions. XPC recognizes helical distortions by binding to unpaired ssDNA opposite DNA lesions. DDB2 binds to UV-induced lesions directly and facilitates efficient recognition by XPC. We show that not only lesion-binding but also timely DDB2 dissociation is required for DNA damage handover to XPC and swift progression of the multistep repair reaction. DNA-binding-induced DDB2 ubiquitylation and ensuing degradation regulate its homeostasis to prevent excessive lesion (re)binding. Additionally, damage handover from DDB2 to XPC coincides with the arrival of the TFIIH complex, which further promotes DDB2 dissociation and formation of a stable XPC-TFIIH damage verification complex. Our results reveal a reciprocal coordination between DNA damage recognition and verification within NER and illustrate that timely repair factor dissociation is vital for correct spatiotemporal control of a multistep repair process.


Assuntos
Dano ao DNA , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Fator de Transcrição TFIIH/metabolismo , Ubiquitina/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Proteínas de Ligação a DNA/genética , Humanos , Fator de Transcrição TFIIH/genética , Ubiquitinação
6.
DNA Repair (Amst) ; 77: 87-95, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30897376

RESUMO

SWI/SNF complexes are among the most studied ATP-dependent chromatin remodeling complexes, mostly due to their critical role in coordinating chromatin architecture and gene expression. Mutations in genes encoding SWI/SNF subunits are frequently observed in a large variety of human cancers, suggesting that one or more of the multiple SWI/SNF functions protect against tumorigenesis. Chromatin remodeling is an integral component of the DNA damage response (DDR), which safeguards against DNA damage-induced genome instability and tumorigenesis by removing DNA damage through interconnected DNA repair and signaling pathways. SWI/SNF has been implicated in facilitating repair of double-strand breaks, by non-homologous end-joining as well as homologous recombination, and repair of helix-distorting DNA damage by nucleotide excision repair. Here, we review current knowledge on SWI/SNF activity in the DDR and discuss the potential of exploiting DDR-related vulnerabilities due to SWI/SNF dysfunction for precision cancer therapy.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Instabilidade Genômica , Neoplasias/genética , Montagem e Desmontagem da Cromatina , Dano ao DNA , Humanos , Neoplasias/metabolismo
7.
Nat Commun ; 9(1): 4067, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30287812

RESUMO

Mutations in SWI/SNF genes are amongst the most common across all human cancers, but efficient therapeutic approaches that exploit vulnerabilities caused by SWI/SNF mutations are currently lacking. Here, we show that the SWI/SNF ATPases BRM/SMARCA2 and BRG1/SMARCA4 promote the expression of p62/GTF2H1, a core subunit of the transcription factor IIH (TFIIH) complex. Inactivation of either ATPase subunit downregulates GTF2H1 and therefore compromises TFIIH stability and function in transcription and nucleotide excision repair (NER). We also demonstrate that cells with permanent BRM or BRG1 depletion have the ability to restore GTF2H1 expression. As a consequence, the sensitivity of SWI/SNF-deficient cells to DNA damage induced by UV irradiation and cisplatin treatment depends on GTF2H1 levels. Together, our results expose GTF2H1 as a potential novel predictive marker of platinum drug sensitivity in SWI/SNF-deficient cancer cells.


Assuntos
DNA Helicases/metabolismo , Reparo do DNA , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Fatores de Transcrição TFII/metabolismo , Fatores de Transcrição/metabolismo , Linhagem Celular , Dano ao DNA , Humanos , Fator de Transcrição TFIIH
8.
Nucleic Acids Res ; 46(18): 9537-9549, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30137419

RESUMO

Sensitivity and resistance of cells to platinum drug chemotherapy are to a large extent determined by activity of the DNA damage response (DDR). Combining chemotherapy with inhibition of specific DDR pathways could therefore improve treatment efficacy. Multiple DDR pathways have been implicated in removal of platinum-DNA lesions, but it is unclear which exact pathways are most important to cellular platinum drug resistance. Here, we used CRISPR/Cas9 screening to identify DDR proteins that protect colorectal cancer cells against the clinically applied platinum drug oxaliplatin. We find that besides the expected homologous recombination, Fanconi anemia and translesion synthesis pathways, in particular also transcription-coupled nucleotide excision repair (TC-NER) and base excision repair (BER) protect against platinum-induced cytotoxicity. Both repair pathways are required to overcome oxaliplatin- and cisplatin-induced transcription arrest. In addition to the generation of DNA crosslinks, exposure to platinum drugs leads to reactive oxygen species production that induces oxidative DNA lesions, explaining the requirement for BER. Our findings highlight the importance of transcriptional integrity in cells exposed to platinum drugs and suggest that both TC-NER and BER should be considered as targets for novel combinatorial treatment strategies.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Cisplatino/efeitos adversos , Cisplatino/química , Neoplasias Colorretais/genética , Reparo do DNA/genética , Replicação do DNA/efeitos dos fármacos , Humanos , Oxaliplatina/efeitos adversos , Oxaliplatina/química , Platina/efeitos adversos , Platina/química , Espécies Reativas de Oxigênio/química
9.
Nucleic Acids Res ; 46(18): 9563-9577, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30165384

RESUMO

The structure-specific ERCC1-XPF endonuclease plays a key role in DNA damage excision by nucleotide excision repair (NER) and interstrand crosslink repair. Mutations in this complex can either cause xeroderma pigmentosum (XP) or XP combined with Cockayne syndrome (XPCS-complex) or Fanconi anemia. However, most patients carry compound heterozygous mutations, which confounds the dissection of the phenotypic consequences for each of the identified XPF alleles. Here, we analyzed the functional impact of individual pathogenic XPF alleles on NER. We show that XP-causing mutations diminish XPF recruitment to DNA damage and only mildly affect global genome NER. In contrast, an XPCS-complex-specific mutation causes persistent recruitment of XPF and the upstream core NER machinery to DNA damage and severely impairs both global genome and transcription-coupled NER. Remarkably, persistence of NER factors at DNA damage appears to be a common feature of XPCS-complex cells, suggesting that this could be a determining factor contributing to the development of additional developmental and/or neurodegenerative features in XP patients.


Assuntos
Síndrome de Cockayne/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Xeroderma Pigmentoso/genética , Alelos , Linhagem Celular , Síndrome de Cockayne/patologia , Dano ao DNA/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/química , Endonucleases/química , Anemia de Fanconi/genética , Anemia de Fanconi/patologia , Genoma Humano/genética , Humanos , Complexos Multiproteicos/química , Complexos Multiproteicos/genética , Mutação/genética , Multimerização Proteica/genética
10.
Data Brief ; 7: 1497-505, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27182547

RESUMO

Sea urchins have specialized adhesive organs called tube feet, which mediate strong but reversible adhesion. Tube feet are composed by a disc, producing adhesive and de-adhesive secretions for substratum attachment, and a stem for movement. After detachment the secreted adhesive remains bound to the substratum as a footprint. Recently, a label-free quantitative proteomic approach coupled with the latest mass-spectrometry technology was used to analyze the differential proteome of Paracentrotus lividus adhesive organ, comparing protein expression levels in the tube feet adhesive part (the disc) versus the non-adhesive part (the stem), and also to profile the proteome of the secreted adhesive (glue). This data article contains complementary figures and results related to the research article "Deciphering the molecular mechanisms underlying sea urchin reversible adhesion: a quantitative proteomics approach" (Lebesgue et al., 2016) [1]. Here we provide a dataset of 1384 non-redundant proteins, their fragmented peptides and expression levels, resultant from the analysis of the tube feet differential proteome. Of these, 163 highly over-expressed tube feet disc proteins (>3-fold), likely representing the most relevant proteins for sea urchin reversible adhesion, were further annotated in order to determine the potential functions. In addition, we provide a dataset of 611 non-redundant proteins identified in the secreted adhesive proteome, as well as their functional annotation and grouping in 5 major protein groups related with adhesive exocytosis, and microbial protection. This list was further analyzed to identify the most abundant protein groups and pinpoint putative adhesive proteins, such as Nectin, the most abundant adhesive protein in sea urchin glue. The obtained data uncover the key proteins involved in sea urchins reversible adhesion, representing a step forward to the development of new wet-effective bio-inspired adhesives.

11.
Biochem J ; 473(14): 2225-37, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27208169

RESUMO

Transthyretin amyloidosis (ATTR) belongs to a class of disorders caused by protein misfolding and aggregation. ATTR is a disabling disorder of autosomal dominant trait, where transthyretin (TTR) forms amyloid deposits in different organs, causing dysfunction of the peripheral nervous system. We previously discovered that amyloid fibrils from ATTR patients are glycated by methylglyoxal. Even though no consensus has been reached about the actual role of methylglyoxal-derived advanced glycation end-products in amyloid diseases, evidence collected so far points to a role for protein glycation in conformational abnormalities, being ubiquitously found in amyloid deposits in Alzheimer's disease, dialysis-related amyloidosis and Parkinson's diseases. Human fibrinogen, an extracellular chaperone, was reported to specifically interact with a wide spectrum of stressed proteins and suppress their aggregation, being an interacting protein with TTR. Fibrinogen is differentially glycated in ATTR, leading to its chaperone activity loss. Here we show the existence of a proteostasis imbalance in ATTR linked to fibrinogen glycation by methylglyoxal.


Assuntos
Neuropatias Amiloides Familiares/metabolismo , Fibrinogênio/química , Fibrinogênio/metabolismo , Amiloide/metabolismo , Glicosilação , Humanos , Espectrometria de Massas , Microscopia de Força Atômica , Chaperonas Moleculares/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
12.
J Proteomics ; 138: 61-71, 2016 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-26926440

RESUMO

UNLABELLED: Marine bioadhesives have unmatched performances in wet environments, being an inspiration for biomedical applications. In sea urchins specialized adhesive organs, tube feet, mediate reversible adhesion, being composed by a disc, producing adhesive and de-adhesive secretions, and a motile stem. After tube foot detachment, the secreted adhesive remains bound to the substratum as a footprint. Sea urchin adhesive is composed by proteins and sugars, but so far only one protein, Nectin, was shown to be over-expressed as a transcript in tube feet discs, suggesting its involvement in sea urchin adhesion. Here we use high-resolution quantitative mass-spectrometry to perform the first study combining the analysis of the differential proteome of an adhesive organ, with the proteome of its secreted adhesive. This strategy allowed us to identify 163 highly over-expressed disc proteins, specifically involved in sea urchin reversible adhesion; to find that 70% of the secreted adhesive components fall within five protein groups, involved in exocytosis and microbial protection; and to provide evidences that Nectin is not only highly expressed in tube feet discs but is an actual component of the adhesive. These results give an unprecedented insight into the molecular mechanisms underlying sea urchin adhesion, and opening new doors to develop wet-reliable, reversible, and ecological biomimetic adhesives. SIGNIFICANCE: Sea urchins attach strongly but in a reversible manner to substratum, being a valuable source of inspiration for industrial and biomedical applications. Yet, the molecular mechanisms governing reversible adhesion are still poorly studied delaying the engineering of biomimetic adhesives. We used the latest mass spectrometry techniques to analyze the differential proteome of an adhesive organ and the proteome of its secreted adhesive, allowing us to uncover the key players in sea urchin reversible adhesion. We demonstrate, that Nectin, a protein previously pointed out as potentially involved in sea urchin adhesion, is not only highly expressed in tube feet discs, but is a genuine component of the secreted adhesive.


Assuntos
Adesivos/metabolismo , Moléculas de Adesão Celular/metabolismo , Paracentrotus/metabolismo , Proteômica , Animais , Nectinas
13.
PLoS One ; 10(7): e0125392, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26147092

RESUMO

Transthyretin amyloidosis is a conformational pathology characterized by the extracellular formation of amyloid deposits and the progressive impairment of the peripheral nervous system. Point mutations in this tetrameric plasma protein decrease its stability and are linked to disease onset and progression. Since non-mutated transthyretin also forms amyloid in systemic senile amyloidosis and some mutation bearers are asymptomatic throughout their lives, non-genetic factors must also be involved in transthyretin amyloidosis. We discovered, using a differential proteomics approach, that extracellular chaperones such as fibrinogen, clusterin, haptoglobin, alpha-1-anti-trypsin and 2-macroglobulin are overrepresented in transthyretin amyloidosis. Our data shows that a complex network of extracellular chaperones are over represented in human plasma and we speculate that they act synergistically to cope with amyloid prone proteins. Proteostasis may thus be as important as point mutations in transthyretin amyloidosis.


Assuntos
Neuropatias Amiloides Familiares/metabolismo , Chaperonas Moleculares/metabolismo , Adulto , Sequência de Aminoácidos , Neuropatias Amiloides Familiares/sangue , Proteínas Sanguíneas/química , Estudos de Casos e Controles , Eletroforese em Gel Bidimensional , Feminino , Humanos , Dados de Sequência Molecular , Proteólise , Proteômica , Homologia de Sequência de Aminoácidos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
14.
Nucleic Acids Res ; 42(13): 8473-85, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24990377

RESUMO

Chromatin compaction of deoxyribonucleic acid (DNA) presents a major challenge to the detection and removal of DNA damage. Helix-distorting DNA lesions that block transcription are specifically repaired by transcription-coupled nucleotide excision repair, which is initiated by binding of the CSB protein to lesion-stalled RNA polymerase II. Using live cell imaging, we identify a novel function for two distinct mammalian ISWI adenosine triphosphate (ATP)-dependent chromatin remodeling complexes in resolving lesion-stalled transcription. Human ISWI isoform SMARCA5/SNF2H and its binding partners ACF1 and WSTF are rapidly recruited to UV-C induced DNA damage to specifically facilitate CSB binding and to promote transcription recovery. SMARCA5 targeting to UV-C damage depends on transcription and histone modifications and requires functional SWI2/SNF2-ATPase and SLIDE domains. After initial recruitment to UV damage, SMARCA5 re-localizes away from the center of DNA damage, requiring its HAND domain. Our studies support a model in which SMARCA5 targeting to DNA damage-stalled transcription sites is controlled by an ATP-hydrolysis-dependent scanning and proofreading mechanism, highlighting how SWI2/SNF2 chromatin remodelers identify and bind nucleosomes containing damaged DNA.


Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Reparo do DNA , Transcrição Gênica , Adenosina Trifosfatases/análise , Adenosina Trifosfatases/química , Linhagem Celular , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/análise , Proteínas Cromossômicas não Histona/química , Dano ao DNA , DNA Helicases/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Histonas/metabolismo , Humanos , Proteínas de Ligação a Poli-ADP-Ribose , Estrutura Terciária de Proteína , Fatores de Transcrição/metabolismo , Raios Ultravioleta
15.
Amyloid ; 19(2): 74-80, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22591216

RESUMO

Familial transthyretin amyloidosis (ATTR) is an autosomal dominant disease characterized by the formation of transthyretin (TTR) amyloid deposits. This crippling and fatal disease is associated with point mutations in TTR, a protein mainly produced in the liver. Hence, liver transplantation is the only treatment capable of halting disease progression. Ideally, liver transplantation should be performed as early as possible in the disease course before significant neurologic disability has been incurred. Early detection of disease before serious pathological lesions occur is crucial for the clinical management of patients and for morbidity delay. Unfortunately, the presence of TTR mutations by itself is not a predictor of disease onset or progression. In the present work, we observed an increased oligomerization of α-synuclein in the saliva of ATTR symptomatic individuals comparatively to asymptomatic carriers of the same TTR mutation and healthy control subjects. Based on this observation, we propose monitoring α-synuclein oligomers in saliva as a biomarker of ATTR progression. Since α-synuclein plays a major role in several neurodegenerative disorders, assessing its oligomerization state in this fluid provides a non-invasive approach to survey these pathologies.


Assuntos
Amiloide/metabolismo , Amiloidose Familiar/metabolismo , Pré-Albumina/metabolismo , Saliva/metabolismo , alfa-Sinucleína/metabolismo , Adolescente , Adulto , Sequência de Aminoácidos , Amiloidose Familiar/genética , Amiloidose Familiar/patologia , Amiloidose Familiar/cirurgia , Biomarcadores/metabolismo , Estudos de Casos e Controles , Progressão da Doença , Feminino , Heterozigoto , Humanos , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/isolamento & purificação , Mapeamento de Peptídeos , Multimerização Proteica , Estrutura Quaternária de Proteína , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Adulto Jovem , alfa-Sinucleína/química , alfa-Sinucleína/isolamento & purificação
16.
Amyloid ; 18(4): 191-9, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22080762

RESUMO

Familial transthyretin amyloidosis (ATTR) is a fatal autosomal dominant disease characterized by the formation of amyloid fibers, mainly composed of transthyretin (TTR). Protein aggregation and amyloid fiber formation are considered concentration dependent processes and since most ATTR patients are heterozygous it is crucial to determine the ratio between mutant and non-mutant TTR forms in human plasma. Using a high resolution mass spectrometry based approach we determined the ratio of TTR forms in ATTR patients, V30M mutation carriers, symptomatic and asymptomatic ones, as well as ATTR patients that received a wild type cadaveric liver transplant. Domino transplanted patients that received a liver from an ATTR patient were also investigated. We found that although wild type TTR is diminished in the plasma of non-transplanted ATTR patients comparatively to healthy subjects, the relationship with the V30M variant does not change with illness progression. Those who received a wild type liver showed no mutant protein while domino transplanted patients presented the same relative amount of V30M as found in asymptomatic and symptomatic individuals. The V30M to wild type TTR ratio in plasma is the same for all ATTR patients studied, showing no variation with disease clinical progression. Our results point to the involvement of additional non-genetic factors on the pathogenesis of this disease.


Assuntos
Amiloide/sangue , Amiloidose Familiar/sangue , Análise de Fourier , Adulto , Sequência de Aminoácidos , Amiloide/genética , Amiloidose Familiar/genética , Amiloidose Familiar/cirurgia , Humanos , Transplante de Fígado , Pessoa de Meia-Idade , Peso Molecular , Fragmentos de Peptídeos/química , Mutação Puntual , Pré-Albumina/genética , Estrutura Quaternária de Proteína , Receptor para Produtos Finais de Glicação Avançada/sangue , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Adulto Jovem
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