RESUMO
Dysfunction of cellular homeostasis can lead to misfolding of proteins thus acquiring conformations prone to polymerization into pathological aggregates. This process is associated with several disorders, including neurodegenerative diseases, such as Parkinson's disease (PD), and endoplasmic reticulum storage disorders (ERSDs), like alpha-1-antitrypsin deficiency (AATD) and hereditary hypofibrinogenemia with hepatic storage (HHHS). Given the shared pathophysiological mechanisms involved in such conditions, it is necessary to deepen our understanding of the basic principles of misfolding and aggregation akin to these diseases which, although heterogeneous in symptomatology, present similarities that could lead to potential mutual treatments. Here, we review: (i) the pathological bases leading to misfolding and aggregation of proteins involved in PD, AATD, and HHHS: alpha-synuclein, alpha-1-antitrypsin, and fibrinogen, respectively, (ii) the evidence linking each protein aggregation to the stress mechanisms occurring in the endoplasmic reticulum (ER) of each pathology, (iii) a comparison of the mechanisms related to dysfunction of proteostasis and regulation of homeostasis between the diseases (such as the unfolded protein response and/or autophagy), (iv) and clinical perspectives regarding possible common treatments focused on improving the defensive responses to protein aggregation for diseases as different as PD, and ERSDs.
Assuntos
Afibrinogenemia/genética , Fibrinogênio/química , Doença de Parkinson/genética , Deficiência de alfa 1-Antitripsina/genética , alfa 1-Antitripsina/química , alfa-Sinucleína/química , Afibrinogenemia/tratamento farmacológico , Afibrinogenemia/metabolismo , Afibrinogenemia/patologia , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Coagulantes/uso terapêutico , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Fibrinogênio/genética , Fibrinogênio/metabolismo , Regulação da Expressão Gênica , Humanos , Fígado/metabolismo , Fígado/patologia , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Inibidores de Proteases/uso terapêutico , Agregados Proteicos/efeitos dos fármacos , Dobramento de Proteína/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , Deficiência de alfa 1-Antitripsina/metabolismo , Deficiência de alfa 1-Antitripsina/patologia , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
Se describieron los efectos hemorrágicos, necróticos y edematosos de 135 pacientes provenientes de los estados Miranda, Aragua, Vargas y Distrito Capital, Venezuela, ocasionados por la mordedura de la serpiente cascabel común venezolana (Crotalus durissus cumanensis), durante los años 1998-2008. Los trastornos hemorrágicos, que tradicionalmente eran casi imperceptibles en los Crotalus venezolanos, hemos encontrado que hay evidencias francas de manifestaciones clínicas como: afibrinogenemia, alargamiento del tiempo de coagulación manual (TCM), tiempo parcial de tromboplastina (TTP) y tiempo de protrombina (TP), lo cual indica la presencia de estas fracciones hemorrágicas en el veneno de cascabeles nacionales. Se apreciaron diferencias entre ambos sexos, siendo predominante en el sexo masculino (82%). Sin embargo ha habido un aumento de incidencia significativa en el sexo femenino (17%). Por grupo etario, se observó predominancia entre 11 a 30 años de edad, en ambos sexos. El sitio de mordedura mayormente afectado fue el miembro superior (58,5%), con un porcentaje no menos significativo de miembros inferiores (40,7%). Estos hallazgos, permiten sugerir que el veneno de algunas serpientes cascabeles comunes en Venezuela, poseen un efecto sistémico sobre el músculo esquelético, y también efectos sobre capilares que generan edema, fenómenos hemorrágicos y necrosis, que habían pasado desapercibidos.
The bleeding, necrotic and edematous Snake bite effects from 135 patients of Miranda, Aragua, Vargas States and Capital District (Venezuela), caused by the Venezuelan common rattlesnake (Crotalus durissus cumanensis) from 1998 to 2008 were described. In bleeding disorders, which traditionally were almost imperceptible in Venezuelan Crotalus, we have found reliable evidence of clinical manifestations such as: afibrinogenemia, lengthening of the manual time of coagulation (MTC), and Partial Time of Thromboplastin (PTT) and Prothrombin time (PT), which indicates the presence of hemorrhagic fractions in the Venezuelan rattlesnakes venoms. There were differences between the sexes, still predominant in male (82%). However, there has been an increase of significant impact on female (17%). By age, there was prevalence between 11 and 30 years old, both male and female. The mostly affected bite si te was upper limb (58,5%), with a no less significant percentage of lower limbs (40,7%). These findings, allowed us to suggest that some rattlesnake venoms have a systemic effect on skeletal muscle, and also effects on capillaries that generate swelling, hemorrhagic phenomena and necrosis.
Assuntos
Humanos , Animais , Masculino , Feminino , Serpentes/classificação , Venenos de Crotalídeos/análise , Afibrinogenemia/metabolismo , Transtornos Hemorrágicos/sangue , Tempo de Tromboplastina Parcial , Venenos/toxicidade , Tempo de Protrombina , Saúde PúblicaRESUMO
The first low-molecular-mass metalloprotease presenting prothrombin activating activity was purified from Bothrops insularis venom and named insularinase A. It is a single-chain protease with a molecular mass of 22 639 Da. cDNA sequence analysis revealed that the disintegrin domain of the precursor protein is post-translationally processed, producing the mature insularinase A. Analysis of its deduced amino acid sequence showed a high similarity with several fibrin(ogen)olytic metalloproteases and only a moderate similarity with prothrombin activators. However, SDS-PAGE of prothrombin after activation by insularinase A showed fragment patterns similar to those generated by group A prothrombin activators, which convert prothrombin into meizothrombin independently of the prothrombinase complex. In addition, insularinase A activates factor X and hydrolyses fibrinogen and fibrin. Chelating agents fully inhibit all insularinase A activities. Insularinase A induced neither detachment nor apoptosis of human endothelial cells and was also not able to trigger an endothelial proinflammatory cell response. Nitric oxide and prostacyclin levels released by endothelial cells were significantly increased after treatment with insularinase A. Our results show that, although its primary structure is related to class P-I fibrin(ogen)olytic metalloproteases, insularinase A is functionally similar to group A prothrombin activators.