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

Publication ,  Journal Article
Patil, H; Tserentsoodol, N; Saha, A; Hao, Y; Webb, M; Ferreira, PA
Published in: Cell Death Dis
July 19, 2012

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.

Duke Scholars

Published In

Cell Death Dis

DOI

EISSN

2041-4889

Publication Date

July 19, 2012

Volume

3

Issue

7

Start / End Page

e355

Location

England

Related Subject Headings

  • Up-Regulation
  • Tubulin
  • Rhodopsin
  • Proteins
  • Photoreceptor Connecting Cilium
  • Neoplasm Proteins
  • Mutation
  • Mice
  • Kidney Tubules
  • Eye Proteins
 

Citation

APA
Chicago
ICMJE
MLA
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Patil, H., Tserentsoodol, N., Saha, A., Hao, Y., Webb, M., & Ferreira, P. A. (2012). Selective loss of RPGRIP1-dependent ciliary targeting of NPHP4, RPGR and SDCCAG8 underlies the degeneration of photoreceptor neurons. Cell Death Dis, 3(7), e355. https://doi.org/10.1038/cddis.2012.96
Patil, H., N. Tserentsoodol, A. Saha, Y. Hao, M. Webb, and P. A. Ferreira. “Selective loss of RPGRIP1-dependent ciliary targeting of NPHP4, RPGR and SDCCAG8 underlies the degeneration of photoreceptor neurons.Cell Death Dis 3, no. 7 (July 19, 2012): e355. https://doi.org/10.1038/cddis.2012.96.
Patil H, Tserentsoodol N, Saha A, Hao Y, Webb M, Ferreira PA. Selective loss of RPGRIP1-dependent ciliary targeting of NPHP4, RPGR and SDCCAG8 underlies the degeneration of photoreceptor neurons. Cell Death Dis. 2012 Jul 19;3(7):e355.
Patil, H., et al. “Selective loss of RPGRIP1-dependent ciliary targeting of NPHP4, RPGR and SDCCAG8 underlies the degeneration of photoreceptor neurons.Cell Death Dis, vol. 3, no. 7, July 2012, p. e355. Pubmed, doi:10.1038/cddis.2012.96.
Patil H, Tserentsoodol N, Saha A, Hao Y, Webb M, Ferreira PA. Selective loss of RPGRIP1-dependent ciliary targeting of NPHP4, RPGR and SDCCAG8 underlies the degeneration of photoreceptor neurons. Cell Death Dis. 2012 Jul 19;3(7):e355.

Published In

Cell Death Dis

DOI

EISSN

2041-4889

Publication Date

July 19, 2012

Volume

3

Issue

7

Start / End Page

e355

Location

England

Related Subject Headings

  • Up-Regulation
  • Tubulin
  • Rhodopsin
  • Proteins
  • Photoreceptor Connecting Cilium
  • Neoplasm Proteins
  • Mutation
  • Mice
  • Kidney Tubules
  • Eye Proteins