RESUMO
Amyotrophic lateral sclerosis is a fatal disease pathologically typified by motor and cortical neurodegeneration as well as microgliosis. The FUS P525L mutation is highly penetrant and causes ALS cases with earlier disease onset and more aggressive progression. To date, how P525L mutations may affect microglia during ALS pathogenesis had not been explored. In this study, we engineered isogenic control and P525L mutant FUS in independent human iPSC lines and differentiated them into microglia-like cells. We report that the P525L mutation causes FUS protein to mislocalize from the nucleus to cytoplasm. Homozygous P525L mutations perturb the transcriptome profile in which many differentially expressed genes are associated with microglial functions. Specifically, the dysregulation of several chemoreceptor genes leads to altered chemoreceptor-activated calcium signaling. However, other microglial functions such as phagocytosis and cytokine release are not significantly affected. Our study underscores the cell-autonomous effects of the ALS-linked FUS P525L mutation in a human microglia model.
Assuntos
Esclerose Lateral Amiotrófica , Células-Tronco Pluripotentes Induzidas , Proteína FUS de Ligação a RNA , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Microglia/metabolismo , Mutação , Proteína FUS de Ligação a RNA/genética , TranscriptomaRESUMO
We present the genomic sequence of Legionella pneumophila, the bacterial agent of Legionnaires' disease, a potentially fatal pneumonia acquired from aerosolized contaminated fresh water. The genome includes a 45-kilobase pair element that can exist in chromosomal and episomal forms, selective expansions of important gene families, genes for unexpected metabolic pathways, and previously unknown candidate virulence determinants. We highlight the genes that may account for Legionella's ability to survive in protozoa, mammalian macrophages, and inhospitable environmental niches and that may define new therapeutic targets.