Identification of a photoreceptor-specific mRNA encoded by the gene responsible for retinal degeneration slow (rds)

Travis, Gabriel H.; Brennan, Miles B.; Danielson, Patria E.; Kozak, Christine A.; Sutcliffe, J. Gregor

doi:10.1038/338070a0

Cited by 360 publications

(144 citation statements)

References 21 publications

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“…Relatively slowly degenerating photoreceptors of Rds mice do not form outer segments due to the lack of structural protein, peripherin-2 (27,28); this requires continuous degradation of multiple proteins otherwise residing in this cellular compartment. Similarly, more rapidly degenerating rods of Rho −/− mice form only rudimentary outer segments, also necessitating the degradation of outer segment-specific proteins (29,30).…”

Section: Gβmentioning

confidence: 99%

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

Lobanova

Finkelstein

Skiba

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Inherited retinal degenerations, caused by mutations in over 100 individual genes, affect approximately 2 million people worldwide. Many of the underlying mutations cause protein misfolding or mistargeting in affected photoreceptors. This places an increased burden on the protein folding and degradation machinery, which may trigger cell death. We analyzed how these cellular functions are affected in degenerating rods of the transducin γ-subunit (Gγ 1 ) knockout mouse. These rods produce large amounts of transducin β-subunit (Gβ 1 ), which cannot fold without Gγ 1 and undergoes intracellular proteolysis instead of forming a transducin βγ-subunit complex. Our data revealed that the most critical pathobiological factor leading to photoreceptor cell death in these animals is insufficient capacity of proteasomes to process abnormally large amounts of misfolded protein. A decrease in the Gβ 1 production in Gγ 1 knockout rods resulted in a significant reduction in proteasomal overload and caused a striking reversal of photoreceptor degeneration. We further demonstrated that a similar proteasomal overload takes place in photoreceptors of other mutant mice where retinal degeneration has been ascribed to protein mistargeting or misfolding, but not in mice whose photoreceptor degenerate as a result of abnormal phototransduction. These results establish the prominence of proteasomal insufficiency across multiple degenerative diseases of the retina, thereby positioning proteasomes as a promising therapeutic target for treating these debilitating conditions. neurodegenerative diseases | protein degradation

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Section: Gβmentioning

confidence: 99%

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

Lobanova

Finkelstein

Skiba

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Although P/rds possesses a clear role in maintaining the structure of rods and cones, insights into its molecular mechanism through protein interactions are quite limited. Currently, P/rds is conjectured to play a significant role in disk morphogenesis and stability (1,11), disk shedding (1,12), and membrane fusion (13,14 Cloning and identification of P/rds orthologs suggests that these proteins share several distinctive features, including four hydrophobic transmembrane domains, a large intradiscal (D2) loop containing seven highly conserved cysteines, and a highly charged cytosolic Cterminal segment (4,15,16). Over 70% of the disease-causing mutations in P/rds are located in the D2 loop, providing evidence of the importance that this region plays in proper protein function.…”

Section: Introductionmentioning

confidence: 99%

Role of the Second Intradiscal Loop of Peripherin/rds in Homo and Hetero Associations

2005

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Peripherin/rds (P/rds) is a disk rim protein that assembles into homo and hetero complexes with its nonglycosylated homologue, Rom-1, to maintain the integrity of the photoreceptor outer segment. Mutations in the rds gene have been identified in a variety of human retinal degenerative diseases. More than 70% of these mutations are located in the second intradiscal (D2) loop, highlighting the functional importance of this region. This study examines the involvement of different regions of the D2 loop in protein associations using a GST pull-down assay and a heterologous coexpression system. The pull-down assay suggests an association of the N-terminal portion (Phe 120 -Phe 187 ) of the D2 loop with Rom-1 as well as with other P/rds molecules. Through peptide competition experiments, the region between Cys 165 and Asn 182 of the D2 loop has been identified as the domain for these associations. In a COS-1 cell heterologous expression system, coexpression of the D2 loop along with the intact P/rds and Rom-1 hindered the association of the two full-length proteins. In contrast to the homo association of P/rds molecules, it seems that the hetero association of P/rds with Rom-1 has a more stringent structural requirement. This work defines the crucial domain of the D2 loop, which mediates homo and hetero associations, specifically the regions that lay between Cys 165 and Asn 182 . Elucidation of the molecular mechanisms behind the protein-protein associations of P/rds and its partners may reveal the pathogenic defects arising from the most common mutations in this gene.Peripherin/rds (P/rds) 1 is a membrane-bound glycoprotein localized along the rim region of disks found in rod and cone outer segments (OSs) (1,2). The importance of this protein was established by a naturally occurring null mutation in the rds gene, identified as retinal degeneration slow (rds). Mice homozygous for this mutation fail to develop OS structures (3,4), while heterozygous rds mice form highly disorganized OSs (5,6). The role of P/rds in photoreceptor integrity has been demonstrated through the link between mutations in the rds gene and human retinal degenerative diseases such as autosomal dominant retinitis pigmentosa (ADRP) and several forms of macular dystrophy (MD) (7-10). Although P/rds possesses a clear role in maintaining the structure of rods and cones, insights into its molecular mechanism through protein interactions are quite limited. Currently, P/rds is conjectured to play a significant role in disk morphogenesis and stability (1,11), disk shedding (1,12), and membrane fusion (13,14 Cloning and identification of P/rds orthologs suggests that these proteins share several distinctive features, including four hydrophobic transmembrane domains, a large intradiscal (D2) loop containing seven highly conserved cysteines, and a highly charged cytosolic Cterminal segment (4,15,16). Over 70% of the disease-causing mutations in P/rds are located in the D2 loop, providing evidence of the importance that this region plays in proper pro...

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“…Rom1 is a related disk-rim protein with 37% overall identity and similar membrane topology to rds (7). Mice homozygous for a knockout mutation in the rom1 gene displayed mild OS dysplasia (8), in contrast to complete absence of OS in rdsϪ͞Ϫ mice (9)(10)(11). Unlike RDS, no mutations in the ROM1 gene alone have been convincingly associated with human retinal disease (12,13).…”

mentioning

confidence: 99%

Deficiency of rds/peripherin causes photoreceptor death in mouse models of digenic and dominant retinitis pigmentosa

Kędzierski

Nusinowitz

Birch

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Retinitis pigmentosa (RP) is a group of inherited blinding diseases caused by mutations in multiple genes including RDS. RDS encodes rds͞peripherin (rds), a 36-kDa glycoprotein in the rims of rod and cone outer-segment (OS) discs. Rom1 is related to rds with similar membrane topology and the identical distribution in OS. In contrast to RDS, no mutations in ROM1 alone have been associated with retinal disease. However, an unusual digenic form of RP has been described. Affected individuals in several families were doubly heterozygous for a mutation in RDS causing a leucine 185 to proline substitution in rds (L185P) and a null mutation in ROM1. Neither mutation alone caused clinical abnormalities. Here, we generated transgenic͞knockout mice that duplicate the amino acid substitutions and predicted levels of rds and rom1 in patients with RDS-mediated digenic and dominant RP. Photoreceptor degeneration in the mouse model of digenic RP was faster than in the wild-type and monogenic controls by histological, electroretinographic, and biochemical analysis. We observed a positive correlation between the rate of photoreceptor loss and the extent of OS disorganization in mice of several genotypes. Photoreceptor degeneration in RDS-mediated RP appears to be caused by a simple deficiency of rds and rom1. The critical threshold for the combined abundance of rds and rom1 is Ϸ60% of wild type. Below this value, the extent of OS disorganization results in clinically significant photoreceptor degeneration. R etinitis pigmentosa (RP) is a family of inherited retinal diseases characterized by progressive night blindness and loss of peripheral vision (1). Pathologically, RP is associated with degeneration of rod photoreceptors. Heterozygous mutations in the RDS gene are a common cause of autosomal dominant RP (2, 3). An example is the RDS P216L-allele (4). RDS encodes rds͞peripherin (rds), a 36-kDa glycoprotein in the rims of rod and cone outer-segment (OS) discs (5, 6). These stacked membranous structures are the sites of photon-capture and reactions of visual transduction. Rom1 is a related disk-rim protein with 37% overall identity and similar membrane topology to rds (7). Mice homozygous for a knockout mutation in the rom1 gene displayed mild OS dysplasia (8), in contrast to complete absence of OS in rdsϪ͞Ϫ mice (9-11). Unlike RDS, no mutations in the ROM1 gene alone have been convincingly associated with human retinal disease (12, 13). However, an unusual digenic form of RP has been described. Affected individuals in four pedigrees were doubly heterozygous for a mutation in RDS causing a leucine 185 to proline substitution in rds (L185P) and a second presumptive null mutation in the unlinked ROM1 gene (13,14). Neither mutation alone caused significant abnormalities.The phenotype in rdsϪ͞Ϫ mutant mice (9, 10) indicates a critical role for rds in the formation of OS. Expression of a chimeric protein in transgenic mice on an rdsϪ͞Ϫ geneticbackground established that rds is 2.5-fold more abundant than rom1, and that the rds-rom1 in...

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Identification of a photoreceptor-specific mRNA encoded by the gene responsible for retinal degeneration slow (rds)

Cited by 360 publications

References 21 publications

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

Role of the Second Intradiscal Loop of Peripherin/rds in Homo and Hetero Associations

Deficiency of rds/peripherin causes photoreceptor death in mouse models of digenic and dominant retinitis pigmentosa

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