RESUMEN
Here, we use a mouse model (DBA/2J) to readdress the location of insult(s) to retinal ganglion cells (RGCs) in glaucoma. We localize an early sign of axon damage to an astrocyte-rich region of the optic nerve just posterior to the retina, analogous to the lamina cribrosa. In this region, a network of astrocytes associates intimately with RGC axons. Using BAX-deficient DBA/2J mice, which retain all of their RGCs, we provide experimental evidence for an insult within or very close to the lamina in the optic nerve. We show that proximal axon segments attached to their cell bodies survive to the proximity of the lamina. In contrast, axon segments in the lamina and behind the eye degenerate. Finally, the Wld(s) allele, which is known to protect against insults to axons, strongly protects against DBA/2J glaucoma and preserves RGC activity as measured by pattern electroretinography. These experiments provide strong evidence for a local insult to axons in the optic nerve.
Asunto(s)
Axones/patología , Glaucoma/fisiopatología , Enfermedades del Nervio Óptico/fisiopatología , Degeneración Retiniana/fisiopatología , Células Ganglionares de la Retina/patología , Degeneración Walleriana/fisiopatología , Animales , Citoprotección/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Electrorretinografía , Femenino , Glaucoma/complicaciones , Glaucoma/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Ratones Mutantes Neurológicos , Ratones Transgénicos , Mutación/genética , Enfermedades del Nervio Óptico/etiología , Enfermedades del Nervio Óptico/patología , Degeneración Retiniana/etiología , Degeneración Retiniana/patología , Factores de Tiempo , Degeneración Walleriana/etiología , Degeneración Walleriana/patología , Proteína X Asociada a bcl-2/genéticaRESUMEN
Small-vessel diseases of the brain underlie 20 to 30 percent of ischemic strokes and a larger proportion of intracerebral hemorrhages. In this report, we show that a mutation in the mouse Col4a1 gene, encoding procollagen type IV alpha1, predisposes both newborn and adult mice to intracerebral hemorrhage. Surgical delivery of mutant mice alleviated birth-associated trauma and hemorrhage. We identified a COL4A1 mutation in a human family with small-vessel disease. We concluded that mutation of COL4A1 may cause a spectrum of cerebrovascular phenotypes and that persons with COL4A1 mutations may be predisposed to hemorrhage, especially after environmental stress.
Asunto(s)
Encéfalo/irrigación sanguínea , Hemorragia Cerebral/genética , Colágeno Tipo IV/genética , Predisposición Genética a la Enfermedad , Mutación , Animales , Encéfalo/patología , Hemorragia Cerebral/etiología , Femenino , Membrana Basal Glomerular/anomalías , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL/genética , Ratones Mutantes , Microcirculación , Linaje , Arteria Renal/anomalías , Arteria Retiniana/anomalías , Factores de Riesgo , Estrés Fisiológico/complicaciones , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/genéticaRESUMEN
Porencephaly is a rare neurological disease, typically manifest in infants, which is characterized by the existence of degenerative cavities in the brain. To investigate the molecular pathogenesis of porencephaly, we studied a mouse mutant that develops porencephaly secondary to focal disruptions of vascular basement membranes. Half of the mutant mice died with cerebral hemorrhage within a day of birth, and approximately 18% of survivors had porencephaly. We show that vascular defects are caused by a semidominant mutation in the procollagen type IV alpha 1 gene (Col4a1) in mice, which inhibits the secretion of mutant and normal type IV collagen. We also show that COL4A1 mutations segregate with porencephaly in human families. Because not all mutant mice develop porencephaly, we propose that Col4a1 mutations conspire with environmental trauma in causing the disease.