Xue Cai

Tubby is required for trafficking G protein-coupled receptors to neuronal cilia

BackgroundTubby is the founding member of the tubby-like family of proteins. The naturally occurring tubby mutation in mice causes retinitis pigmentosa, hearing loss and obesity. Tubby has been proposed to function as an accessory factor in ciliary trafficking. We directly examined a role for tubby in ciliary trafficking in vivo.MethodsWe used immunofluoresence labeling to examine the subcellular localization of rhodopsin, somatostatin receptor 3 (SSTR3) and melanin concentrating hormone receptor 1 (MCHR1), all of which are G protein-coupled receptors (GPCR), in the retina and brain of wild type (WT) and tubby mutant mice.ResultsIn tubby mouse retina, rhodopsin is not fully transported across the connecting cilia to the outer segments with ensuing photoreceptor degeneration. In the tubby mouse brain, SSTR3 and MCHR1 fail to localize at the neuronal primary cilia in regions where these receptors play critical roles in neural signaling. The tubby mutant does not manifest a generalized defect in ciliogenesis or protein trafficking.ConclusionsTubby plays a critical role in trafficking select GPCRs to the cilia. This role is reminiscent of tubby-like proteins 1 and 3, which have been proposed to facilitate trafficking of rhodopsin and select GPCRs in photoreceptors and the developing neural tube, respectively. Thus tubby-like proteins may be generally involved in transciliary trafficking of GPCRs.

Sustained protection against photoreceptor degeneration in tubby mice by intravitreal injection of nanoceria

We previously reported that nanoceria can slow retinal degeneration in the tubby mouse for two weeks by multiple systemic injections. However, the long-term protection of retinal structure and function by directly deliver of nanoceria to the eye had not been explored. In this study, 172 ng of nanoceria in 1 μl saline (1 mm) were intravitreally injected into tubby P7 pups and assays were performed at P28, P49, P80 and P120. The expression of antioxidant associated genes and photoreceptor-specific genes was significantly up regulated, the mislocalization of rod and cone opsins was decreased, and retinal structure and function were protected. These findings demonstrate that nanoceria can function as catalytic antioxidants in vivo and may be broad spectrum therapeutic agents for multiple types of ocular diseases.

Oxidative stress: The achilles' heel of neurodegenerative diseases of the retina

Age-related macular degeneration (AMD) is the leading cause of blindness among adults in the developed countries. It is characterized by the progressive loss of central vision. AMD is classified into two forms: dry and wet. Dry AMD involves the accumulation of deposits in the RPE and Bruchs membrane; Wet AMD is characterized by neovascularization in the choroid. Whether the two forms of AMD share the same mechanism for the disease development is presently not clear. Oxidative stress, inflammation, and ER-stress are the common modes for the pathogenesis of AMD. In addition, other risk factors and several signaling pathways have been implicated as causative factors of AMD. In this paper, the mechanisms underlying AMD, risk factors involved in the pathology, representative animal models, and therapeutic treatment strategies are reviewed.

Diabetic Retinopathy: Animal Models, Therapies, and Perspectives

Diabetic retinopathy (DR) is one of the major complications of diabetes. Although great efforts have been made to uncover the mechanisms underlying the pathology of DR, the exact causes of DR remain largely unknown. Because of multifactor involvement in DR etiology, currently no effective therapeutic treatments for DR are available. In this paper, we review the pathology of DR, commonly used animal models, and novel therapeutic approaches. Perspectives and future directions for DR treatment are discussed.