PMID- 31401765
OWN - NLM
STAT- MEDLINE
DCOM- 20201105
LR  - 20201105
IS  - 1559-1182 (Electronic)
IS  - 0893-7648 (Linking)
VI  - 57
IP  - 2
DP  - 2020 Feb
TI  - Calpain Activation Is the Major Cause of Cell Death in Photoreceptors Expressing 
      a Rhodopsin Misfolding Mutation.
PG  - 589-599
LID - 10.1007/s12035-019-01723-5 [doi]
AB  - The majority of mutations in rhodopsin (RHO) cause misfolding of the protein and 
      has been linked to degeneration of photoreceptor cells in the retina. A lot of 
      attention has been set on targeting ER stress for the development of new 
      therapies for inherited retinal degeneration caused by mutations in the RHO gene. 
      Nevertheless, the cell death pathway activated by RHO misfolded protein is still 
      debated. In this study, we analyzed the retina of the knock-in mouse expressing 
      the P23H misfolded mutant RHO. We found persistent unfolded protein response 
      (UPR) during degeneration. Interestingly, long-term stimulation of the PERK 
      branch of ER stress had a protective effect by phosphorylating nuclear factor 
      erythroid 2-related factor 2 (NRF2) transcription factor, associated with 
      antioxidant responses. Otherwise, we provide evidence that increased 
      intracellular calcium and activation of calpains strongly correlated with rod 
      photoreceptor cell death. By blocking calpain activity, we significantly 
      decreased the activation of caspase-7 and apoptosis-inducing factor (AIF), two 
      cell death effectors, and cell demise, and effectively protected the retina from 
      degeneration caused by the P23H dominant mutation in RHO.
FAU - Comitato, Antonella
AU  - Comitato A
AD  - Department of Life Sciences, University of Modena and Reggio Emilia, via Campi, 
      287, 41125, Modena, Italy.
FAU - Schiroli, Davide
AU  - Schiroli D
AD  - Department of Life Sciences, University of Modena and Reggio Emilia, via Campi, 
      287, 41125, Modena, Italy.
FAU - Montanari, Monica
AU  - Montanari M
AD  - Department of Life Sciences, University of Modena and Reggio Emilia, via Campi, 
      287, 41125, Modena, Italy.
FAU - Marigo, Valeria
AU  - Marigo V
AUID- ORCID: 0000-0002-4428-2084
AD  - Department of Life Sciences, University of Modena and Reggio Emilia, via Campi, 
      287, 41125, Modena, Italy. valeria.marigo@unimore.it.
LA  - eng
GR  - call for proposals 2013 on Retinitis Pigmentosa/Fondazione Roma/
GR  - transMed, MSCA-ITN-2017-765441/H2020/
GR  - GGP11210, GGP14180/Fondazione Telethon/
PT  - Journal Article
DEP - 20190810
PL  - United States
TA  - Mol Neurobiol
JT  - Molecular neurobiology
JID - 8900963
RN  - 0 (Protein Kinase Inhibitors)
RN  - 9009-81-8 (Rhodopsin)
RN  - EC 2.7.11.1 (PERK kinase)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
RN  - EC 3.4.22.- (Calpain)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - *Apoptosis/drug effects
MH  - Calcium/metabolism
MH  - Calpain/*metabolism
MH  - Endoplasmic Reticulum Stress/drug effects
MH  - Enzyme Activation/drug effects
MH  - Intracellular Space/metabolism
MH  - Mice, Inbred C57BL
MH  - Mutation/*genetics
MH  - Photoreceptor Cells, Vertebrate/*metabolism
MH  - *Protein Folding/drug effects
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Retinal Degeneration/pathology
MH  - Rhodopsin/chemistry/*genetics/metabolism
MH  - Unfolded Protein Response/drug effects
MH  - eIF-2 Kinase/metabolism
OTO - NOTNLM
OT  - GSK2606414A
OT  - PD150606
OT  - Rod
OT  - Spectrin
OT  - Z-VAD-FMK
OT  - adRP
OT  - eIF2alpha
EDAT- 2019/08/12 06:00
MHDA- 2020/11/06 06:00
CRDT- 2019/08/12 06:00
PHST- 2019/04/26 00:00 [received]
PHST- 2019/07/26 00:00 [accepted]
PHST- 2019/08/12 06:00 [pubmed]
PHST- 2020/11/06 06:00 [medline]
PHST- 2019/08/12 06:00 [entrez]
AID - 10.1007/s12035-019-01723-5 [pii]
AID - 10.1007/s12035-019-01723-5 [doi]
PST - ppublish
SO  - Mol Neurobiol. 2020 Feb;57(2):589-599. doi: 10.1007/s12035-019-01723-5. Epub 2019 
      Aug 10.