Journal article
The PDE6 mutation in the rd10 retinal degeneration mouse model causes protein mislocalization and instability and promotes cell death through increased ion influx
The Journal of biological chemistry, Vol.293(40), pp.15332-15346
10/05/2018
DOI: 10.1074/jbc.RA118.004459
PMCID: PMC6177582
PMID: 30126843
Abstract
The retinal degeneration model rd10 contains a missense mutation of the catalytic PDE6 β subunit, which hydrolyzes cGMP in response to light. This model produces cell death more slowly than others caused by PDE6 loss of function, making it of particular interest for studying potential therapeutics. We used morphology, biochemistry, and single-cell physiology to examine the mechanism of rd10 degeneration. Our results show that the mutation produces no alteration of Pde6b RNA but does dramatically decrease maximal and basal PDE6 activity, apparently caused by a decrease in protein stability and transport. The enzymatic properties of the remaining mutant PDE6 appear to be nearly normal. We demonstrate that an increase in free cGMP, which would result from decreased PDE6 activity and serve to increase opening of the cGMP-gated channels and calcium influx, is an underlying cause of cell death: degeneration of rd10/Cngb1−/− double mutants is slower than the parent rd10 line. Paradoxically, degeneration in rd10/Cngb1−/− is also slower than in Cngb1−/−. This rescue is correlated with a lowering of cGMP content in Cngb1−/− retinas and suggests that it may be caused by mislocalization of active PDE6. Single-cell recordings from rd10 rods show that the rates of rise and decay of the response are significantly slower; simulations indicate that these changes are primarily the result of the decrease in PDE6 concentration and rod collecting area. Together, these results provide insights into the complex mechanisms that underlie rd10-mediated retinal degeneration and a cautionary note for analysis of therapeutic interventions.
Details
- Title: Subtitle
- The PDE6 mutation in the rd10 retinal degeneration mouse model causes protein mislocalization and instability and promotes cell death through increased ion influx
- Creators
- Tian Wang - From the Zilkha Neurogenetic Institute and Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-2821Jürgen Reingruber - the Institut de Biologie, Group of Computational Biology and Applied Mathematics, École Normale Supérieure, 75005 Paris, FranceMichael L Woodruff - the Department of Integrative Biology and Physiology, UCLA, Los Angeles, California 90095-1606Anurima Majumder - the Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, andAndres Camarena - From the Zilkha Neurogenetic Institute and Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-2821Nikolai O Artemyev - the Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, andGordon L Fain - the Department of Integrative Biology and Physiology, UCLA, Los Angeles, California 90095-1606Jeannie Chen - From the Zilkha Neurogenetic Institute and Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-2821
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.293(40), pp.15332-15346
- DOI
- 10.1074/jbc.RA118.004459
- PMID
- 30126843
- PMCID
- PMC6177582
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000053, name: HHS | NIH | National Eye Institute (NEI), award: EY12155, EY027193, EY01844, EY10843, EY027387
- Language
- English
- Date published
- 10/05/2018
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
- Record Identifier
- 9984070670102771
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