RESUMO
Mutations in GBA1 encountered in Gaucher disease are a leading risk factor for Parkinson disease and associated Lewy body disorders. Many GBA1 mutation carriers, especially those with severe or null GBA1 alleles, have earlier and more progressive parkinsonism. To model the effect of partial glucocerebrosidase deficiency on neurological progression in vivo, mice with a human A53T α-synuclein (SNCAA53T) transgene were crossed with heterozygous null gba mice (gba+/-). Survival analysis of 84 mice showed that in gba+/-//SNCAA53T hemizygotes and homozygotes, the symptom onset was significantly earlier than in gba+/+//SNCAA53T mice (p-values 0.023-0.0030), with exacerbated disease progression (p-value <0.0001). Over-expression of SNCAA53T had no effect on glucocerebrosidase levels or activity. Immunoblotting demonstrated that gba haploinsufficiency did not lead to increased levels of either monomeric SNCA or insoluble high molecular weight SNCA in this model. Immunohistochemical analyses demonstrated that the abundance and distribution of SNCA pathology was also unaltered by gba haploinsufficiency. Thus, while the underlying mechanism is not clear, this model shows that gba deficiency impacts the age of onset and disease duration in aged SNCAA53T mice, providing a valuable resource to identify modifiers, pathways and possible moonlighting roles of glucocerebrosidase in Parkinson pathogenesis.
Assuntos
Doença de Gaucher/genética , Glucosilceramidase/genética , Haploinsuficiência , Doença de Parkinson/genética , alfa-Sinucleína/genética , Idade de Início , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Doença de Gaucher/complicações , Glucosilceramidase/deficiência , Glucosilceramidas/análise , Heterozigoto , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Mutação , Doença de Parkinson/etiologia , Psicosina/análogos & derivados , Psicosina/análise , Transgenes , alfa-Sinucleína/análise , alfa-Sinucleína/deficiência , alfa-Sinucleína/metabolismo , beta-Glucosidase/deficiência , beta-Glucosidase/genéticaRESUMO
Over 13 years, the Celebremos la Vida (CLV) program has offered free breast examinations, mammograms, and cervical cancer screenings to uninsured Latinas residing in the Northern Virginia suburbs of Washington, D.C. The CLV program aims to educate participants on the importance of breast self-examination and regular cancer screening for the early detection of breast and cervical cancer.