P<scp>ROGRESS</scp> T<scp>OWARD</scp> U<scp>NDERSTANDING THE</scp> G<scp>ENETIC AND</scp> B<scp>IOCHEMICAL</scp> M<scp>ECHANISMS OF</scp> I<scp>NHERITED</scp> P<scp>HOTORECEPTOR</scp> D<scp>EGENERATIONS</scp>

Pacione, Laura; Szego, Michael J.; Ikeda, Shinya; Nishina, Patsy M.; McInnes, Roderick R.

doi:10.1146/annurev.neuro.26.041002.131416

Cited by 138 publications

(85 citation statements)

References 172 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The mutations we examined cause retinal degeneration either as a primary disorder of rod photoreceptors (RHO, rhodopsin) or as a disorder of both rod and cone photoreceptors (RPGR, retinitis pigmentosa GTPase regulator; RDS (also called PRPH2), retinal degeneration slow or peripherin 2; TULP1, tubby-like protein 1; ATXN7 (also called SCA7), ataxin 7 or spinocerebellar ataxia 7). Most cause rates of degeneration that are consistent with a one-hit exponential decay model of cell death 5,6,9 .…”

Section: Measuring Rates Of Degenerationmentioning

confidence: 53%

“…We then compared rates of photoreceptor degeneration caused by functionally equivalent mutations in five different genes with highly conserved functions in mammalian retina [7][8][9] across five species with different LSPs. The mutations we examined cause retinal degeneration either as a primary disorder of rod photoreceptors (RHO, rhodopsin) or as a disorder of both rod and cone photoreceptors (RPGR, retinitis pigmentosa GTPase regulator; RDS (also called PRPH2), retinal degeneration slow or peripherin 2; TULP1, tubby-like protein 1; ATXN7 (also called SCA7), ataxin 7 or spinocerebellar ataxia 7).…”

Section: Measuring Rates Of Degenerationmentioning

confidence: 99%

“…nal photoreceptors (RetNet; see URL below); these affect virtually all areas of metabolism and all parts of the cell [7][8][9] .…”

mentioning

confidence: 99%

See 2 more Smart Citations

Lifespan and mitochondrial control of neurodegeneration

et al. 2004

View full text Add to dashboard Cite

We examine the allometric (comparative scaling) relationships between rates of neurodegeneration resulting from equivalent mutations in a diverse group of genes from five mammalian species with different maximum lifespan potentials. In both retina and brain, rates of neurodegeneration vary by as much as two orders of magnitude and are strongly correlated with maximum lifespan potential and rates of formation of mitochondrial reactive oxygen and nitrogen species (RONS). Cell death in these disorders is directly or indirectly regulated by the intrinsic mitochondrial cell death pathway. Mitochondria are the main source of RONS production and integrate cellular stress signals to coordinate the intrinsic pathway. We propose that these two functions are intimately related and that steadystate RONS-mediated signaling or damage to the mitochondrial stress-integration machinery is the principal factor setting the probability of cell death in response to a diverse range of cellular stressors. This provides a new and unifying framework for investigating neurodegenerative disorders.Cell death in inherited neurodegenerative disorders most commonly occurs by apoptosis 1-4 . The evidence is often indirect and inferred on the basis of characteristic morphological changes, such as chromatin compaction and cell shrinkage, or evidence of caspase activation, but in many cases it is more reliably based on multiple lines of evidence [1][2][3][4] . Caspase-independent cell death also occurs, although the precise mechanisms are less well understood and evidence that this occurs in inherited neurodegenerations is sparse. In these disorders, cell death occurs with a probability that is constant through part or all of the adult lifespan, consistent with a steady-state (one-hit or exponential kinetics) rather than a cumulative damage model 5,6 . The retina is a particularly well understood model of neurodegeneration. Mutations in more than 100 genes are known to cause neurodegeneration of retinal photoreceptors (RetNet; see URL below); these affect virtually all areas of metabolism and all parts of the cell 7-9 .Two main pathways lead to the activation of cysteine proteases or caspases that execute the apoptotic death program [10][11][12] . The extrinsic pathway involves cell-surface signaling complexes (e.g., Fas or FasL), which trigger the cell death cascade by activating caspase 8 and downstream caspases. The intrinsic, or mitochondrial, pathway controls activation of caspase 9, through the adaptor molecule Apaf-1, by regulating release of cytochrome c from mitochondria. Proapoptotic and antiapoptotic members of the Bcl-2 family and various stress and survival signals regulate the release of cytochrome c. Proapoptotic signals can also release proteins such as Smac and Omi, which antagonize IAP (inhibitor of apoptosis) proteins to activate cell death caspases, from the mitochondrial intermembrane space.Evidence from animal models of human photoreceptor degeneration suggests that the mitochondrial, rather than the extrinsic, cell death pa...

show abstract

Section: Measuring Rates Of Degenerationmentioning

confidence: 53%

Section: Measuring Rates Of Degenerationmentioning

confidence: 99%

See 1 more Smart Citation

Lifespan and mitochondrial control of neurodegeneration

et al. 2004

View full text Add to dashboard Cite

show abstract

“…Many of the mutations in ninaE are dominant [216,217], as is the case for human ADRP disease resulting from mutations in rhodopsin [209,210,218]. The dominance may be attributable to misfolding of the rhodopsin derivatives, which in turn interferes with the posttranslational maturation of wild-type rhodopsin [216,217,219].…”

Section: Retinal Degenerationmentioning

confidence: 99%

Phototransduction and retinal degeneration in Drosophila

Wang

Montell

2007

Pflugers Arch - Eur J Physiol

261

303

View full text Add to dashboard Cite

Drosophila visual transduction is the fastest known G-protein-coupled signaling cascade and has therefore served as a genetically tractable animal model for characterizing rapid responses to sensory stimulation. Mutations in over 30 genes have been identified, which affect activation, adaptation, or termination of the photoresponse. Based on analyses of these genes, a model for phototransduction has emerged, which involves phosphoinoside signaling and culminates with opening of the TRP and TRPL cation channels. Many of the proteins that function in phototransduction are coupled to the PDZ containing scaffold protein INAD and form a supramolecular signaling complex, the signalplex. Arrestin, TRPL, and Gα q undergo dynamic light-dependent trafficking, and these movements function in long-term adaptation. Other proteins play important roles either in the formation or maturation of rhodopsin, or in regeneration of phosphatidylinositol 4,5-bisphosphate (PIP 2 ), which is required for the photoresponse. Mutation of nearly any gene that functions in the photoresponse results in retinal degeneration. The underlying bases of photoreceptor cell death are diverse and involve mechanisms such as excessive endocytosis of rhodopsin due to stable rhodopsin/arrestin complexes and abnormally low or high levels of Ca 2+ . Drosophila visual transduction appears to have particular relevance to the cascade in the intrinsically photosensitive retinal ganglion cells in mammals, as the photoresponse in these latter cells appears to operate through a remarkably similar mechanism.

show abstract

“…Disruptions of these normal gene expression patterns cause photoreceptor degenerations. (Pacione, et al, 2003, Rattner, et al, 1999, Tan, et al, 2001) Transcription factors are integration points for signal transduction networks that orchestrate development. Homeobox transcription-factor genes are expressed in the earliest primordial eye tissue and are essential for vertebrate eye development (i.e.…”

Section: Introductionmentioning

confidence: 99%

FIZ1 is expressed during photoreceptor maturation, and synergizes with NRL and CRX at rod-specific promoters in vitro

Mali

Zhang

Hoerauf

et al. 2007

Experimental Eye Research

View full text Add to dashboard Cite

FIZ1 (Flt-3 Interacting Zinc-finger) interacts and co-purifies with the rod-specific transcription factor NRL (Neural Retina Leucine zipper). We hypothesize that FIZ1 is part of an interface between cell-specific factors, like NRL, and more ubiquitous regulatory networks that vary the absolute expression levels of some rod-specific genes (i.e. Rhodopsin). As part of an ongoing exploration of FIZ1's role in neural retina, in vivo, we have taken the first look at FIZ1 expression in the developing mouse retina during the retinal maturation period. Using the normal C57/B6 mouse as a model, multiple approaches were used including: immunoblotting, immunohistochemistry, and quantitative real-time PCR. Functional implications of FIZ1/NRL interaction, on NRL-and CRX-mediated activation of the Rhodopsin (Rho) and cGMPphosphodiesterase β-subunit gene (PDE6B) promoters, were examined by co-transfection assays. Immunoblot analysis revealed that FIZ1 protein levels were lowest in immature mouse neural retina (P0). FIZ1 concentration increased at least ten-fold as the neural retina matured to the adult state (P21 and later). Immunohistochemical comparison of immature post-natal and mature adult retina revealed increasing FIZ1 protein in photoreceptors, the inner plexiform layer, and the ganglion cell layer. Total retinal Fiz1 mRNA content increased as the neural retina matured. The expected increase in Rho mRNA level was also monitored as a genetic marker of photoreceptor maturation. In transient co-transfection assays of CV1 cells, FIZ1 synergized with NRL to activate transcription from the Rho and PDE6B gene promoters with some differences. In the case of the Rho promoter, FIZ1 synergized when both NRL and CRX were present. With the PDE6B promoter, FIZ1 synergized with NRL alone, and the inclusion of CRX decreased this synergy.Conclusions-These findings support previous evidence that FIZ1 is present in rodphotoreceptors. (Co-immunoprecipitation from nuclear-protein extracts with rod-specific NRL) FIZ1 expression increases in the neural retina during the retinal maturation period. Additionally, in vitro experiments demonstrate that FIZ1 has the potential to significantly increase the NRLmediated activation of photoreceptor-specific promoters. While CRX is not a strong activator of the PDE6B promoter, alone or with NRL, CRX decreased the synergy of NRL with FIZ1.

show abstract

PROGRESS TOWARD UNDERSTANDING THE GENETIC AND BIOCHEMICAL MECHANISMS OF INHERITED PHOTORECEPTOR DEGENERATIONS

Cited by 138 publications

References 172 publications

Lifespan and mitochondrial control of neurodegeneration

Lifespan and mitochondrial control of neurodegeneration

Phototransduction and retinal degeneration in Drosophila

FIZ1 is expressed during photoreceptor maturation, and synergizes with NRL and CRX at rod-specific promoters in vitro

Contact Info

Product

Resources

About