RESUMEN
Many genetic neurological disorders exhibit variable expression within affected families, often exemplified by variations in disease age at onset. Epistatic effects (i.e. effects of modifier genes on the disease gene) may underlie this variation, but the mechanistic basis for such epistatic interactions is rarely understood. Here we report a novel epistatic interaction between SPAST and the contiguous gene DPY30, which modifies age at onset in hereditary spastic paraplegia, a genetic axonopathy. We found that patients with hereditary spastic paraplegia caused by genomic deletions of SPAST that extended into DPY30 had a significantly younger age at onset. We show that, like spastin, the protein encoded by SPAST, the DPY30 protein controls endosomal tubule fission, traffic of mannose 6-phosphate receptors from endosomes to the Golgi, and lysosomal ultrastructural morphology. We propose that additive effects on this pathway explain the reduced age at onset of hereditary spastic paraplegia in patients who are haploinsufficient for both genes.
Asunto(s)
Epistasis Genética/genética , Mutación/genética , Proteínas Nucleares/genética , Paraplejía Espástica Hereditaria/genética , Espastina/genética , Adulto , Edad de Inicio , Antígenos CD8/genética , Antígenos CD8/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Células HeLa/metabolismo , Células HeLa/ultraestructura , Humanos , Proteína 1 de la Membrana Asociada a los Lisosomas/metabolismo , Proteína 1 de la Membrana Asociada a los Lisosomas/ultraestructura , Lisosomas/metabolismo , Lisosomas/ultraestructura , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Proteínas Nucleares/metabolismo , Proteínas Nucleares/ultraestructura , Transporte de Proteínas/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
The cell-invasive, trypomastigote form of Trypanosoma cruzi exhibits a unique relationship with lysosomes in target host cells. In contrast to many intracellular pathogens that are adept at avoiding contact with lysosomes, T. cruzi requires transient residence within this acidic organelle for productive infection. The low pH environment of lysosomes facilitates parasite egress from the vacuole and delivery into the host cytosol, a critical step in the T. cruzi developmental program. Recent studies also suggest that early lysosome fusion with invading or recently internalized parasites is critical for cellular retention of parasites. To ensure targeting to host cell lysosomes, T. cruzi trypomastigotes exploit two distinct modes of invasion that rapidly converge in the cell. In this chapter, we summarize the recent progress and changing views regarding the role of host cell lysosomes in the T. cruzi infection process where our discussion is limited to invasion of nonprofessional phagocytic cells.
