RESUMEN
Vacuolar protein sorting 35 (VPS35), the core component of the retromer complex which regulates endosomal trafficking, is genetically linked with Parkinson's disease (PD). Impaired vision is a common non-motor manifestation of PD. Here, we show mouse retinas with VPS35-deficient rods exhibit synapse loss and visual deficit, followed by progressive degeneration concomitant with the emergence of Lewy body-like inclusions and phospho-α-synuclein (P-αSyn) aggregation. Ultrastructural analyses reveal VPS35-deficient rods accumulate aggregates in late endosomes, deposited as lipofuscins bound to P-αSyn. Mechanistically, we uncover a protein network of VPS35 and its interaction with HSC70. VPS35 deficiency promotes sequestration of HSC70 and P-αSyn aggregation in late endosomes. Microglia which engulf lipofuscins and P-αSyn aggregates are activated, displaying autofluorescence, observed as bright dots in fundus imaging of live animals, coinciding with pathology onset and progression. The Rod∆Vps35 mouse line is a valuable tool for further mechanistic investigation of αSyn lesions and retinal degenerative diseases.
Asunto(s)
Degeneración Retiniana , Proteínas de Transporte Vesicular , alfa-Sinucleína , Animales , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Proteínas de Transporte Vesicular/metabolismo , Proteínas de Transporte Vesicular/genética , Ratones , Degeneración Retiniana/genética , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Células Fotorreceptoras Retinianas Bastones/metabolismo , Células Fotorreceptoras Retinianas Bastones/patología , Endosomas/metabolismo , Microglía/metabolismo , Microglía/patología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Retina/metabolismo , Retina/patología , Ratones Noqueados , Modelos Animales de Enfermedad , Humanos , Sinapsis/metabolismo , Sinapsis/patología , MasculinoRESUMEN
Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. Dry AMD has unclear etiology and no treatment. Lipid-rich drusen are the hallmark of dry AMD. An AMD mouse model and insights into drusenogenesis are keys to better understanding of this disease. Chloride intracellular channel 4 (CLIC4) is a pleomorphic protein regulating diverse biological functions. Here we show that retinal pigment epithelium (RPE)-specific Clic4 knockout mice exhibit a full spectrum of functional and pathological hallmarks of dry AMD. Multidisciplinary longitudinal studies of disease progression in these mice support a mechanistic model that links RPE cell-autonomous aberrant lipid metabolism and transport to drusen formation.
Asunto(s)
Canales de Cloruro/genética , Degeneración Macular/genética , Proteínas Mitocondriales/genética , Mutación/genética , Epitelio Pigmentado de la Retina/metabolismo , Animales , Muerte Celular , Canales de Cloruro/deficiencia , Modelos Animales de Enfermedad , Fondo de Ojo , Homeostasis , Metabolismo de los Lípidos , Degeneración Macular/diagnóstico por imagen , Degeneración Macular/fisiopatología , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Mitocondriales/deficiencia , Especificidad de Órganos/genética , Drusas Retinianas/complicaciones , Drusas Retinianas/diagnóstico por imagen , Drusas Retinianas/patología , Epitelio Pigmentado de la Retina/diagnóstico por imagen , Epitelio Pigmentado de la Retina/fisiopatología , Epitelio Pigmentado de la Retina/ultraestructura , Factores de Riesgo , Transcripción Genética , Visión Ocular/fisiologíaRESUMEN
PURPOSE: To use micro-ribonucleic acid (microRNA) profiles in the vitreous for differential diagnosis of primary vitreoretinal lymphoma and uveitis. DESIGN: Prospective cross-sectional study. METHODS: This prospective cross-sectional study included 17 diffuse large B-cell primary vitreoretinal lymphoma and 12 uveitis patients. The supernatant of ocular fluid was subjected to total RNA extraction, followed by complementary deoxyribonucleic acid (cDNA) synthesis. Selected samples (primary vitreoretinal lymphoma, n = 3; uveitis, n = 3) were arrayed by a real-time polymerase chain reaction (RT-PCR)-based microRNA panel that detects 168 human mature microRNAs. The markers promising in distinct levels between uveitis and lymphoma were further tested for in all the other 23 samples by individual RT-PCR analysis. RESULTS: Of 168 microRNAs in the array, 66.5% were detectable with consistent higher microRNA-484, microRNA-197, and microRNA-132 in the primary vitreoretinal lymphoma vitreous and higher microRNA-155, microRNA-200c, and microRNA-22* in the uveitic ocular fluids. The results were normalized by different combinations of 7 control microRNAs (microRNA-103, microRNA-191, microRNA-42-5p, microRNA-16, microRNA-425, microRNA-93, and microRNA-451). After optimization, normalization against microRNA-16 was equally as reliable as the average of the 7 control microRNAs. Individual assays of all samples supported the pattern yielded from the array analysis. But only microRNA-155 was significantly higher in the uveitic vitreous compared to that with lymphoma. CONCLUSIONS: Mature microRNAs are detectable in ocular fluid samples. Primary vitreoretinal B-cell lymphoma and uveitis might be characterized by distinct microRNA signatures. Quantification of ocular microRNA-155 might be helpful in the differential diagnosis of these 2 diseases.