Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78
Marina S. Gorbatyuk,Tessa B. Knox,Matthew M. LaVail,Oleg S. Gorbatyuk,Syed Mohammed Noorwez,William W. Hauswirth,Jonathan H. Lin,Nicholas Muzyczka,Alfred S. Lewin +8 more
TLDR
The preservation of photoreceptor function resulting from elevated levels of BiP is due to suppression of apoptosis rather than to a promotion of rhodopsin folding, and the preservation of vision in ADRP rats is preserved.Abstract:
The P23H mutation within the rhodopsin gene (RHO) causes rhodopsin misfolding, endoplasmic reticulum (ER) stress, and activates the unfolded protein response (UPR), leading to rod photoreceptor degeneration and autosomal dominant retinitis pigmentosa (ADRP). Grp78/BiP is an ER-localized chaperone that is induced by UPR signaling in response to ER stress. We have previously demonstrated that BiP mRNA levels are selectively reduced in animal models of ADRP arising from P23H rhodopsin expression at ages that precede photoreceptor degeneration. We have now overexpressed BiP to test the hypothesis that this chaperone promotes the trafficking of P23H rhodopsin to the cell membrane, reprograms the UPR favoring the survival of photoreceptors, blocks apoptosis, and, ultimately, preserves vision in ADRP rats. In cell culture, increasing levels of BiP had no impact on the localization of P23H rhodopsin. However, BiP overexpression alleviated ER stress by reducing levels of cleaved pATF6 protein, phosphorylated eIF2α and the proapoptotic protein CHOP. In P23H rats, photoreceptor levels of cleaved ATF6, pEIF2α, CHOP, and caspase-7 were much higher than those of wild-type rats. Subretinal delivery of AAV5 expressing BiP to transgenic rats led to reduction in CHOP and photoreceptor apoptosis and to a sustained increase in electroretinogram amplitudes. We detected complexes between BiP, caspase-12, and the BH3-only protein BiK that may contribute to the antiapoptotic activity of BiP. Thus, the preservation of photoreceptor function resulting from elevated levels of BiP is due to suppression of apoptosis rather than to a promotion of rhodopsin folding.read more
Citations
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Journal ArticleDOI
Targeting the unfolded protein response in disease
TL;DR: Recent advances in the design of novel compounds and therapeutic strategies to manipulate levels of ER stress in disease are discussed.
Journal ArticleDOI
ER stress and the unfolded protein response in neurodegeneration
Claudio Hetz,Smita Saxena +1 more
TL;DR: The latest advances in defining the functional contribution of ER stress to brain diseases are discussed, including novel evidence that relates the UPR to synaptic function, which has implications for cognition and memory.
Journal ArticleDOI
Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases
Claudio Hetz,Bertrand Mollereau +1 more
TL;DR: An overview of the most recent findings addressing the biological relevance of ER stress in the nervous system is provided.
Journal ArticleDOI
Retinitis Pigmentosa: Genes and Disease Mechanisms
Francesco Parmeggiani,Francesco Sorrentino,Diego Ponzin,Vanessa Barbaro,Stefano Ferrari,Enzo Di Iorio +5 more
TL;DR: Which genes are involved in the genesis of RP and how mutations can lead to retinal degeneration are reviewed to reveal important information with respect to the likelihood of disease development and choices of therapy.
Journal ArticleDOI
Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement
Artur V. Cideciyan,Samuel G. Jacobson,William A. Beltran,Alexander Sumaroka,Malgorzata Swider,Simone Iwabe,Alejandro J. Roman,Melani B. Olivares,Sharon B. Schwartz,András M. Komáromy,András M. Komáromy,William W. Hauswirth,Gustavo D. Aguirre +12 more
TL;DR: It is shown that gene therapy improves vision for at least 3 y, but photoreceptor degeneration progresses unabated in humans, and in the canine model, the same result occurs when treatment is at the disease stage equivalent to humans.
References
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Journal ArticleDOI
ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals.
TL;DR: It is found that the ER chaperone BiP/GRP78 binds ATF6 and dissociates in response to ER stress and that dissociation of BiP during ER stress allows ATF6 to be transported to the Golgi.
Journal ArticleDOI
IRE1 Signaling Affects Cell Fate During the Unfolded Protein Response
Jonathan H. Lin,Han Li,Douglas Yasumura,Hannah R. Cohen,Chao Zhang,Barbara Panning,Kevan M. Shokat,Matthew M. LaVail,Peter Walter +8 more
TL;DR: There is a causal link between the duration of UPR branch signaling and life or death cell fate after ER stress, and key findings from studies in cell culture were recapitulated in photoreceptors expressing mutant rhodopsin in animal models of retinitis pigmentosa.
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Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation.
Ramachandra Reddy,Changhui Mao,Peter Baumeister,Richard C. Austin,Randal J. Kaufman,Amy S. Lee +5 more
TL;DR: Evidence is provided that a subpopulation of GRP78 can exist as an ER transmembrane protein, as well as co-localize with caspase-7, as confirmed by fluorescence microscopy and this effect can be reversed by addition of dATP in a cell-free system.
Journal ArticleDOI
Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78
Rammohan V. Rao,Alyson Peel,Anna Logvinova,Gabriel del Rio,Evan Hermel,Takanori Yokota,Paul C. Goldsmith,Lisa M. Ellerby,H. Michael Ellerby,Dale E. Bredesen +9 more
TL;DR: A novel protective role for GRP78 is defined in preventing ER stress‐induced cell death and addition of (d)ATP dissociates this complex and may facilitate movement of caspase‐12 into the cytoplasm to set in motion the cytosolic component of the ER stress-induced apoptotic cascade.
Journal ArticleDOI
Role of the unfolded protein response regulator GRP78/BiP in development, cancer, and neurological disorders.
TL;DR: The discovery of surface localization of GRP78 in cancer cells reveals potential novel function, interaction with cell-surface receptors, and possible therapeutic implications and mouse models reveal that GRP 78 controls maturation and secretion of neuronal factors for proper neural migration and offers neuroprotection.