Résumé
Background: Creutzfeldt-Jakob disease (CJD) is a form of transmissible spongiform encephalopathy, in which a prion protein (PrP Sc) accumulates in the brain of affected individuals. Chile has a prevalence of CJD that is more than twice than in the rest of the world and has the highest rate of familial forms. These later forms are associated with the heterozygocity of codon 200 of PrP protein gene. Aim: To search susceptibility genetic markers of CJD in members of families affected by CJD. Material and methods: A blood sample was obtained from 50 individuals pertaining to four families affected by CJD. DNA from peripheral mononuclear cells was amplified by polymerase chain reaction and sequenced for the gene that codifies PrP protein. Results: In family A, 21 of 23 members were homozygotes for codon 129 (Met/Met) and eight were simultaneously heterozygotes for codon 200 (Glu/Lys). In family B, six of nine members were homozygotes for codon 129, five were heterozygotes for codon 200 and four had both mutations. In family C, the four analyzed subjects were homozygotes for codon 129 and two were simultaneously heterozygotes for codon 200. In family D, nine of 14 members were homozygotes for codon 129 and two were simultaneously homozygotes for codon 200. No family had polymorphisms for codon 219. Conclusions: Thirty two percent of analyzed subjects were homozygotes for codon 129 and heterozygotes for codon 200, condition that defines the genetic susceptibility to acquire CJD. The dominant tendency of these genotypes could explain the higher incidence of CJF in Chile.
Sujets)
Femelle , Humains , Mâle , Codon/génétique , Maladie de Creutzfeldt-Jakob/génétique , Mutation/génétique , Prions/génétique , Séquence d'acides aminés , Séquence nucléotidique , Chili , Marqueurs génétiques , Prédisposition génétique à une maladie , Génotype , Pedigree , Réaction de polymérisation en chaîne , Protéines PrPC/génétique , Protéines PrPSc/génétiqueRésumé
Prion diseases are fatal neurodegenerative disorders associated with the conversion of the cellular prion protein (PrPC) into a pathologic isoform. Although the physiological function of PrPC remains unknown, evidence relates PrPC to copper metabolism and oxidative stress as suggested by its copper-binding properties in the N-terminal octapeptide repeat region. This region also reduces copper ions in vitro, and this reduction ability is associated with the neuroprotection exerted by the octarepeat region against copper in vivo. In addition, the promoter region of the PrPC gene contains putative metal response elements suggesting it may be regulated by heavy metals. Here we address some of the evidence that support a physiological link between PrPC and copper. Also, in vivo experiments suggesting the physiological relevance of PrPC interaction with heparan sulfate proteoglycans are discussed.
Sujets)
Animaux , Rats , Cuivre/métabolisme , Stress oxydatif/physiologie , Protéines PrPC/métabolisme , Protéoglycanes à sulfate d'héparane/métabolisme , Liaison aux protéines , Protéines PrPC/génétique , Maladies à prions/métabolismeRésumé
A doença de Creutzfeldt-Jakob (CJD) é uma forma de demência pré-senil de rápida evolução, geralmente fatal em um ano. Casos autóctones no Brasil têm sido raramente descritos assim como achados de ressonância magnética. Mulher, natural de Ponta Grossa PR, branca , 54 anos , foi admitida no serviço em outubro de 2001 com quadro de amaurose bilateral cortical progressiva desde há 1 mês do internamento. Nunca viajou ao exterior e foi somente submetida a uma cirurgia de redução do estômago, para obesidade. História familial sem relato de casos semelhantes. Logo após o internamento a paciente desenvolveu quadro de disfasia mista, hemiparesia flácida direita, com movimentos coreoatetóticos e crises parciais motoras. Paciente evoluiu com quadro demencial progressivo; atualmente, acamada, torporosa, dependente de alimentação enteral, recebendo mepacrina, fenitoína e clorpromazina , estabilizando o quadro até final de maio de 2002. Exames laboratoriais negativos ou normais. Pesquisa de proteína 14-3-3 no líquor foi positiva; enolase-neurônio-específica no líquor foi normal. Estudo genético do gen PRNP não revelou mutação descrita anteriormente. EEG (23/10/2001) revelou intensa atividade irritativa hemisfério cerebral esquerdo. Estudo de ressonância magnética revelou áreas de hipersinal em T2 e FLAIR em regiões temporal esquerda e bioccipital; gânglios da base normal. Imagens de DWI mostraram hipersinal nas mesmas áreas.Outro EEG (15/03/2002) revelou padrão periódico de ondas trifásicas sugestivos de CJD. A paciente fez uso de mepacrina associado a clorpromazina com aparente estabilização do quadro, até seu óbito por complicações infecciosas pulmonares em abril de 2003.
Sujets)
Femelle , Humains , Adulte d'âge moyen , Maladie de Creutzfeldt-Jakob/diagnostic , Imagerie par résonance magnétique de diffusion/méthodes , Antipaludiques/usage thérapeutique , Neuroleptiques/usage thérapeutique , Technique de Western , Maladie de Creutzfeldt-Jakob/traitement médicamenteux , Maladie de Creutzfeldt-Jakob/génétique , Échocardiographie , Électroencéphalographie , Issue fatale , Spectroscopie par résonance magnétique , Phénothiazines/usage thérapeutique , /génétique , Protéines PrPC/génétique , Mépacrine/usage thérapeutiqueRésumé
PrPc é uma glicoproteína de 35 KDa, bastante conservada entre as espécies e essencial no processo de transmissão e patogênese de várias doenças neurodegenerativas como a encefalopatia espongiforme bovina e a doença de Creutzfedt-Jacob (PRUSINER, 1991). Embora sua função fisiológica ainda seja desconhecida, sabe-se que a patogênese das doenças priônicas requer a sua expressão e é freqüentemente acompanhada do acúmulo no cérebro de uma isoforma anormal de PrPc, designada PrPsc (GABIZON e cols, 1997). Interessado nos possíveis papéis fisiológicos da proteína PrPc, nosso grupo tem se dedicado a estudar as interações que PrPc realiza com outras moléculas...
Sujets)
Animaux , Souris , Apoptose , Maladies neurodégénératives/physiopathologie , Techniques in vitro , Mémoire , Protéines PrPC/physiologie , Protéines PrPC/génétique , Protéines PrPC/pathogénicité , Dosage biologique , Technique de Western , Milieux de cultureRésumé
A conversäo da proteína príon celular (PrPc) em sua isoforma anormal PrPsc está associada a uma série de doenças neurodegenerativas, genericamente designadas por doenças priônicas. Embora a literatura tenha enfatizado o estudo do PrPsc e o mecanismo de propagaçäo das doenças de príon, pouco tem sido feito para o entendimento do papel fisiológico do PrPc. Em 1997 nosso grupo descreveu um receptor/ligante para o PrPc utilizando o princípio da hidropaticidade complementar. Neste trabalho isolamos e identificamos este ligante de PrPc como sendo a STI-1 (Stress Inducible Protein-1). In vitro, a STI-1 interage com o PrPc de maneira específica, saturável e com alta afinidade (Kd=8x10-8M)...
Sujets)
Animaux , Lapins , Maladies neurodégénératives/génétique , Matrice extracellulaire , Techniques in vitro , Protéines PrPC/génétique , Protéines PrPC/pathogénicité , Récepteur laminine , Technique de Western , Test ELISA , Technique d'immunofluorescence , Vecteurs génétiques/analyseRésumé
Prions have been extensively studied since they represent a new class of infectious agents in which a protein, PrPsc (prion scrapie), appears to be the sole component of the infectious particle. They are responsible for transmissible spongiform encephalopathies, which affect both humans and animals. The mechanism of disease propagation is well understood and involves the interaction of PrPsc with its cellular isoform (PrPc) and subsequently abnormal structural conversion of the latter. PrPc is a glycoprotein anchored on the cell surface by a glycosylphosphatidylinositol moiety and expressed in most cell types but mainly in neurons. Prion diseases have been associated with the accumulation of the abnormally folded protein and its neurotoxic effects; however, it is not known if PrPc loss of function is an important component. New efforts are addressing this question and trying to characterize the physiological function of PrPc. At least four different mouse strains in which the PrP gene was ablated were generated and the results regarding their phenotype are controversial. Localization of PrPc on the cell membrane makes it a potential candidate for a ligand uptake, cell adhesion and recognition molecule or a membrane signaling molecule. Recent data have shown a potential role for PrPc in the metabolism of copper and moreover that this metal stimulates PrPc endocytosis. Our group has recently demonstrated that PrPc is a high affinity laminin ligand and that this interaction mediates neuronal cell adhesion and neurite extension and maintenance. Moreover, PrPc-caveolin-1 dependent coupling seems to trigger the tyrosine kinase Fyn activation. These data provide the first evidence for PrPc involvement in signal transduction