RESUMO
As a protein with complex domain structure and roles in kinase, GTPase and scaffolding, LRRK2 is believed to be an important orchestration node leading to several cascades of signal transduction rather than one specific pathway. LRRK2 variants were found to be associated with Parkinson's disease, Crohn's disease and leprosy. Here we disrupt LRRK2 in zebrafish and found hyperactivity rather than hypoactivity in adult zebrafish mutants. By RNA-seq we found genes involved in infectious disease and immunological disease were notably affected. Functional studies also revealed a weakened antibacterial response in LRRK2 mutant. This mutant can be further explored for revealing molecular mechanisms and modeling of LRRK2 related diseases.
Assuntos
Hipercinese/etiologia , Imunidade/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Proteínas de Peixe-Zebra/genética , Animais , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Comportamento Animal , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/imunologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/fisiologia , Atividade Motora/genética , Mutagênese Sítio-Dirigida , Análise de Sequência de RNA , Peixe-Zebra , Proteínas de Peixe-Zebra/imunologia , Proteínas de Peixe-Zebra/fisiologiaRESUMO
The aim of this paper is to review the use of genetics in palaeomicrobiology, and to highlight the importance of understanding past diseases. Palaeomicrobiology is the study of disease pathogens in skeletal and mummified remains from archaeological contexts. It has revolutionarised our understanding of health in the past by enabling a deeper knowledge of the origins and evolution of many diseases that have shaped us as a species. Bacterial diseases explored include tuberculosis, leprosy, bubonic plague, typhoid, syphilis, endemic and epidemic typhus, trench fever, and Helicobacter pylori. Viral diseases discussed include influenza, hepatitis B, human papilloma virus (HPV), human T-cell lymphotrophic virus (HTLV-1) and human immunodeficiency virus (HIV). Parasitic diseases investigated include malaria, leishmaniasis, Chagas' disease, roundworm, whipworm, pinworm, Chinese liver fluke, fleas and lice. Through a better understanding of disease origins and their evolution, we can place into context how many infectious diseases are changing over time, and so help us estimate how they may change in the future.
Assuntos
Doenças Transmissíveis/genética , Genética Populacional/métodos , Paleopatologia/métodos , Infecções Bacterianas/genética , Infecções Bacterianas/microbiologia , DNA/genética , DNA/isolamento & purificação , Fósseis , Humanos , Múmias , Doenças Parasitárias/genética , Doenças Parasitárias/parasitologia , Viroses/genética , Viroses/virologiaRESUMO
As predictions show infectious diseases were, are and will be, responsible for a significant percentage (more than 12% in the year 2030) of deaths worldwide. Infectious diseases are, according to J.B.S. Haldane's theory, the major agent determining natural selection, as they lead to elimination of more susceptible people and only leave to survive these, who are more resistant. It has been revealed that susceptibility to pathogens varies among ethnic groups. Explanation of this phenomenon can be found in the human genome. Standard genetic analysis led to identification of several gene variants which modulate susceptibility to particular infectious disease as well as its progression. HLA genes encoding major histocompatibility complex are one of the most interesting ones as they are reported to influence the susceptibility to a wide range of pathogens. It is also proved that in several cases many other genes take part in modulation of clinical outcome of the diseases. Alleles conferring partial or total protection against disease development have already been identified. This review presents results of selected research concerning genetically determined susceptibility to malaria, cholera, leprosy and HIV.
Assuntos
Infecções Bacterianas/genética , Toxinas Bacterianas/genética , Enterotoxinas/genética , Predisposição Genética para Doença/genética , Antígenos HLA-DR/genética , Cólera/genética , Regulação Bacteriana da Expressão Gênica , HIV/genética , Humanos , Hanseníase/genética , Malária/genética , Polimorfismo GenéticoRESUMO
The scope of the tuberculosis (TB) epidemic in the world today is enormous, with about 30 million active cases. Current research into preventing the spread of TB is focused on development of new drugs to inactivate Mycobacterium tuberculosis, the causative agent of TB, as well as on identifying the critical steps of host defense to infection with Mycobacteria, which might also yield therapeutic targets. Our infection genomics approach toward the latter strategy has been to isolate and characterize a mouse gene, Bcg (Nramp1), which controls natural susceptibility to infection with Mycobacteria, as well as Salmonella and Leishmania. Through comparative genomics, we have identified the homologous human NRAMP1 gene, alleles of which are now being used for tests of linkage with TB and leprosy.