PMID- 26207309
OWN - NLM
STAT- MEDLINE
DCOM- 20151013
LR  - 20181113
IS  - 1552-5783 (Electronic)
IS  - 0146-0404 (Print)
IS  - 0146-0404 (Linking)
VI  - 56
IP  - 8
DP  - 2015 Jul
TI  - Targeting Caspase-12 to Preserve Vision in Mice With Inherited Retinal 
      Degeneration.
PG  - 4725-33
LID - 10.1167/iovs.15-16924 [doi]
AB  - PURPOSE: The unfolded protein response is known to contribute to the inherited 
      retinal pathology observed in T17M rhodopsin (T17M) mice. Recently it has been 
      demonstrated that the endoplasmic reticulum stress-associated caspase-12 is 
      activated during progression of retinal degeneration in different animal models. 
      Therefore, we wanted to explore the role of caspase-12 in the mechanism of 
      retinopathy in T17M mice and determine if inhibiting apoptosis in this way is a 
      viable approach for halting retinal degeneration. METHODS: One, two-, and 
      three-month-old C57BL6/J, caspase-12-/-, T17M, and T17M caspase-12-/- mice were 
      analyzed by scotopic ERG, spectral-domain optical coherence tomography (SD-OCT), 
      histology, quantitative (q)RT-PCR, and Western blot of retinal RNA and protein 
      extracts. Calpain and caspase-3/7 activity assays were measured in postnatal (P) 
      day 30 retinal extracts. RESULTS: Caspase-12 ablation significantly prevented a 
      decline in the a- and b-wave ERG amplitudes in T17M mice during three months, 
      increasing the amplitudes from 232% to 212% and from 160% to 138%, respectively, 
      as compared to T17M retinas. The SD-OCT results and photoreceptor row counts 
      demonstrated preservation of retinal structural integrity and postponed 
      photoreceptor cell death. The delay in photoreceptor cell death was due to 
      significant decreases in the activity of caspase-3/7 and calpain, which 
      correlated with an increase in calpastatin expression. CONCLUSIONS: We validated 
      caspase-12 as a therapeutic target, ablation of which significantly protects T17M 
      photoreceptors from deterioration. Although the inhibition of apoptotic activity 
      alone was not sufficient to rescue T17M photoreceptors, in combination with other 
      nonapoptotic targets, caspase-12 could be used to treat inherited retinopathy.
FAU - Bhootada, Yogesh
AU  - Bhootada Y
AD  - Department of Vision Sciences University of Alabama at Birmingham, Birmingham, 
      Alabama, United States.
FAU - Choudhury, Shreyasi
AU  - Choudhury S
AD  - Department of Cell Biology and Anatomy, University of North Texas Health Science 
      Center, North Texas Eye Research Institute, Fort Worth, Texas, United States.
FAU - Gully, Clark
AU  - Gully C
AD  - Department of Vision Sciences University of Alabama at Birmingham, Birmingham, 
      Alabama, United States.
FAU - Gorbatyuk, Marina
AU  - Gorbatyuk M
AD  - Department of Vision Sciences University of Alabama at Birmingham, Birmingham, 
      Alabama, United States.
LA  - eng
GR  - R01 EY020905/EY/NEI NIH HHS/United States
GR  - R01EY020905/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - 63231-63-0 (RNA)
RN  - EC 3.4.22.- (Casp12 protein, mouse)
RN  - EC 3.4.22.- (Caspase 12)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Blotting, Western
MH  - Caspase 12/biosynthesis/*genetics
MH  - Disease Models, Animal
MH  - Electroretinography
MH  - Female
MH  - *Gene Expression Regulation
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - RNA/*genetics
MH  - Real-Time Polymerase Chain Reaction
MH  - Retina/metabolism/*pathology
MH  - Retinal Degeneration/diagnosis/*genetics/metabolism
MH  - Tomography, Optical Coherence
PMC - PMC4516015
EDAT- 2015/07/25 06:00
MHDA- 2015/10/16 06:00
PMCR- 2016/01/01
CRDT- 2015/07/25 06:00
PHST- 2015/07/25 06:00 [entrez]
PHST- 2015/07/25 06:00 [pubmed]
PHST- 2015/10/16 06:00 [medline]
PHST- 2016/01/01 00:00 [pmc-release]
AID - 2411354 [pii]
AID - IOVS-15-16924 [pii]
AID - 10.1167/iovs.15-16924 [doi]
PST - ppublish
SO  - Invest Ophthalmol Vis Sci. 2015 Jul;56(8):4725-33. doi: 10.1167/iovs.15-16924.