Selective loss of RPGRIP1-dependent ciliary targeting of NPHP4, RPGR and SDCCAG8 underlies the degeneration of photoreceptor neurons.

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The retinitis pigmentosa GTPase regulator (RPGR) and nephrocystin-4 (NPHP4) comprise two key partners of the assembly complex of the RPGR-interacting protein 1 (RPGRIP1). Mutations in RPGR and NPHP4 are linked to severe multisystemic diseases with strong retinal involvement of photoreceptor neurons, whereas those in RPGRIP1 cause the fulminant photoreceptor dystrophy, Leber congenital amaurosis (LCA). Further, mutations in Rpgrip1 and Nphp4 suppress the elaboration of the outer segment compartment of photoreceptor neurons by elusive mechanisms, the understanding of which has critical implications in uncovering the pathogenesis of syndromic retinal dystrophies. Here we show RPGRIP1 localizes to the photoreceptor connecting cilium (CC) distally to the centriole/basal body marker, centrin-2 and the ciliary marker, acetylated-α-tubulin. NPHP4 abuts proximally RPGRIP1, RPGR and the serologically defined colon cancer antigen-8 (SDCCAG8), a protein thought to partake in the RPGRIP1 interactome and implicated also in retinal-renal ciliopathies. Ultrastructurally, RPGRIP1 localizes exclusively throughout the photoreceptor CC and Rpgrip1(nmf247) photoreceptors present shorter cilia with a ruffled membrane. Strikingly, Rpgrip1(nmf247) mice without RPGRIP1 expression lack NPHP4 and RPGR in photoreceptor cilia, whereas the SDCCAG8 and acetylated-α-tubulin ciliary localizations are strongly decreased, even though the NPHP4 and SDCCAG8 expression levels are unaffected and those of acetylated-α-tubulin and γ-tubulin are upregulated. Further, RPGRIP1 loss in photoreceptors shifts the subcellular partitioning of SDCCAG8 and NPHP4 to the membrane fraction associated to the endoplasmic reticulum. Conversely, the ciliary localization of these proteins is unaffected in glomeruli or tubular kidney cells of Rpgrip1(nmf247), but NPHP4 is downregulated developmentally and selectively in kidney cortex. Hence, RPGRIP1 presents cell type-dependent pathological effects crucial to the ciliary targeting and subcellular partitioning of NPHP4, RPGR and SDCCAG8, and acetylation of ciliary α-tubulin or its ciliary targeting, selectively in photoreceptors, but not kidney cells, and these pathological effects underlie photoreceptor degeneration and LCA.





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Patil, H, N Tserentsoodol, A Saha, Y Hao, M Webb and PA Ferreira (2012). Selective loss of RPGRIP1-dependent ciliary targeting of NPHP4, RPGR and SDCCAG8 underlies the degeneration of photoreceptor neurons. Cell Death Dis, 3. p. e355. 10.1038/cddis.2012.96 Retrieved from

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Paulo Alexandre Ferreira

Associate Professor in Ophthalmology

The long-term goal of our research program is twofold. The first is to understand the interplay between intracellular signaling, intracellular trafficking and proteostasis in health and disease; the second is to uncover molecular players and mechanisms partaking in such processes that are amenable to therapeutic intervention in a variety of disease states. Presently, our research efforts are centered on dissecting the roles of two disease-associated protein interactomes assembled by the Ran-binding protein 2 (RanBP2) and the retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) in several neuronal cell types of the retina and brain that often undergo neurodegeneration upon a multiplicity of diseases with distinct etiologies.

The RanBP2 is a large and modular 358 kDa protein scaffold, which assembles a large multifunctional complex and acts a signal integrator of molecular and subcellular signaling and trafficking pathways critical to neuronal survival or function. Mutations or deficits in RanBP2 are linked to a variety of diseases processes ranging from neurodegeneration and necrosis to stress signaling and cancer. RanBP2 modulates the assembly or disassembly of several protein complexes with apparent disparate functions and implicated in molecular processes, such as nucleocytoplasmic and microtubule-based intracellular trafficking of proteins or organelles, protein homeostasis and biogenesis, modulation of protein-protein interactions (e.g. sumoylation), and control of cell division. Interdisciplinary approaches ranging from single molecule analysis to cell-based assays and genetically modified mouse models are employed to dissect selective cell type-dependent roles of proteins modulated dynamically by RanBP2 and underlying mechanisms in healthy and disease states.

The RPGRIP1 is also a modular protein, which associates directly with molecular partners, such as the retinitis pigmentosa GTPase regulator (RPGR) and nephrocystin-4 (NPHP4). Human mutations in the genes encoding RPGRIP1, RPGR and NPHP4 lead to severe ocular-renal, syndromic and non-syndromic retinal or renal diseases. These lead ultimately to blindness, loss of kidney function or both. Emerging data from our laboratory implicate the RPGRIP1 interactome in the regulation of the tethering, targeting, exiting and/or transport of selective retinal-renal and pre-ciliary components from the endoplasmic reticulum compartment to cilia. These processes serve as molecular determinants to the formation of subcellular structures/compartments that are critical to photoreceptor or tubular kidney cell functions . Current work is directed at dissecting: i) the biological and pathological roles of components of the RPGRIP1 interactome in retinal and kidney functions; ii) the molecular, cellular and pathophysiological bases of allelic-specific mutations and genetic heterogeneity affecting components of the RPGRIP1 interactome; iii) the identification of therapeutic targets and mechanisms dependent on the functions of the RPGRIP1 assembly complex and therapeutic approaches to delay the onset or progression of degeneration of photoreceptor, tubular kidney cells or both.

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