NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage

Xiong, Wenjun; Garfinkel, Alexandra E. MacColl; Li, Yiqing; Benowitz, Larry I.; Cepko, Constance L.

doi:10.1172/jci79735

Cited by 230 publications

(244 citation statements)

References 97 publications

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“…In RP, degeneration and, subsequently, death of diseased, mutant rods leads to the non-cell autonomous loss of wild-type cones (2,10,11). However, it is not known if degenerating rods have non-cell autonomous effects on the rods surrounding them.…”

Section: Discussionmentioning

confidence: 99%

Genetic rescue models refute nonautonomous rod cell death in retinitis pigmentosa

Koch

Duong

Hsu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Fig. 3. Restoration of PDE6b expression rescues rods and partially restores OS length, in a dose-dependent fashion, and prevents cone death. Pde6b STOP / Pde6b H620Q , Pde6g::CreERT2 mice were injected with 25, 50, or 100 μg/g BW tamoxifen to rescue 30% (T30), 50% (T50), or 70% (T70) of rods, respectively; untreated mutants (mut) and wild-type mice (Pde6b + /Pde6b H620Q , Pde6g::CreERT2, WT) were not injected. Tamoxifen injections were in 1-mo-old mice; at 9 mo of age, retinas were sectioned and immunolabeled. (A) Antibodies: rhodopsin or PDE6b (rod OSs, red) and arrestin (cones, green). Hoechst dye, nuclei, blue. Arrows, arrestin-immunopositive cone cell bodies; arrowheads, arrestin-immunopositive cone OSs. (B) Rhodopsin and arrestin immunolabeled sections were quantitatively analyzed for ONL thickness, cone number, rod OS length and cone IS + OS length. Gray dots, individual mice (n = 4 for each group); horizontal black lines, group means. Treated and untreated groups were compared by a linear regression model: ***P < 0.001. IS, inner segment; ONL, outer nuclear layer; OS, outer segment. (Scale bar, 15 μm.)

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Section: Discussionmentioning

confidence: 99%

Genetic rescue models refute nonautonomous rod cell death in retinitis pigmentosa

Koch

Duong

Hsu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The primary cell death drivers, Ca 2+ and cGMP toxicity arising from PDE6 dysfunction, were not reversed by Sirt6 inhibition. Continued cone cell death may be due to loss of RdCVF after death of rods (73)(74)(75)(76)(77) or because of a reduction in the antioxidant transcription factor NRF2 (78,79). Achieving long-term efficacy is a universal limitation for most gene therapy interventions.…”

Section: Pde6bmentioning

confidence: 99%

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

Zhang¹,

Du²,

Justus³

et al. 2016

Journal of Clinical Investigation

119

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Retinitis pigmentosa (RP) encompasses a diverse group of Mendelian disorders leading to progressive degeneration of rods and then cones. For reasons that remain unclear, diseased RP photoreceptors begin to deteriorate, eventually leading to cell death and, consequently, loss of vision. Here, we have hypothesized that RP associated with mutations in phosphodiesterase-6 (PDE6) provokes a metabolic aberration in rod cells that promotes the pathological consequences of elevated cGMP and Ca 2+, which are induced by the Pde6 mutation. Inhibition of sirtuin 6 (SIRT6), a histone deacetylase repressor of glycolytic flux, reprogrammed rods into perpetual glycolysis, thereby driving the accumulation of biosynthetic intermediates, improving outer segment (OS) length, enhancing photoreceptor survival, and preserving vision. In mouse retinae lacking Sirt6, effectors of glycolytic flux were dramatically increased, leading to upregulation of key intermediates in glycolysis, TCA cycle, and glutaminolysis. Both transgenic and AAV2/8 gene therapy-mediated ablation of Sirt6 in rods provided electrophysiological and anatomic rescue of both rod and cone photoreceptors in a preclinical model of RP. Due to the extensive network of downstream effectors of Sirt6, this study motivates further research into the role that these pathways play in retinal degeneration. Because reprogramming metabolism by enhancing glycolysis is not gene specific, this strategy may be applicable to a wide range of neurodegenerative disorders.Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration , were challenging to interpret because of negative effects on synaptic transmission (45). We therefore altered our approach to limit ablation of Sirt6 to rod photoreceptors with an inducible gene disruption strategy. Using this model, we tested whether upregulation of glycolytic flux through Sirt6 knockout can preserve both rod and cone photoreceptors in a preclinical, Pde6-associated RP model. The Journal of Clinical Investigation R E S E A R C H A R T I C L E ResultsGeneration of experimental and control groups. The third most common cause of autosomal recessive RP is deficiency in the PDE6 enzyme, which controls the depolarization state of rods by regulating cGMP levels (9, 46-48). An established preclinical model for RP involves a homozygous point mutation (H620Q) in the gene months by increasing glucose uptake and utilization for NADPH production in 4 different mouse models of RP (11,12). In our report, we propose a similar strategy that improves both survival and function of degenerating rods and cones. We hypothesized that Pde6-associated RP provokes a metabolic aberration in the rod cells that forces them to succumb to the consequences of elevated cGMP and Ca 2+ via cyclic nucleotide-gated (CNG) channels and Na + /Ca 2+ -K + exchangers (36-39). The histone deacetylase sirtuin 6 (SIRT6) is a transcriptional repressor of glycolytic enzymes that has been extensively studied in the context of metabolism and cancer biology (40). Normally, S...

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“…Oxidative stress results in release of NRF2 from its cytoplasmic-binding partner KELCH-like ECH-associated protein 1 (KEAP1), allowing translocation of NRF2 into the nucleus, where it activates transcription by binding to antioxidant response elements in the regulatory regions of phase II genes, including Hmox1, Nqo1, Gclm, Slc7a11, Srxn1, and Sod1/2/3 (55, 56). NRF2 signaling has been proposed as a therapeutic candidate for photoreceptor degeneration, neurodegenerative disorders, diabetes, cancer, and cardiovascular diseases because it provides extensive cellular protection via activation of multiple genes (57)(58)(59)(60). In fact, BG-12 (dimethyl fumarate) was recently approved by the Food and Drug Administration as an NRF2 activator to treat the relapsing/remitting form of multiple sclerosis (61,62).…”

Section: Discussionmentioning

confidence: 99%

MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

Nagar

Noveral

Trudler

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Gaining mechanistic insight into interaction between causative factors of complex multifactorial diseases involving photoreceptor damage might aid in devising effective therapies. Oxidative stress is one of the potential unifying mechanisms for interplay between genetic and environmental factors that contribute to photoreceptor pathology. Interestingly, the transcription factor myocyte enhancer factor 2d (MEF2D) is known to be important in photoreceptor survival, as knockout of this transcription factor results in loss of photoreceptors in mice. Here, using a mild light-induced retinal degeneration model, we show that the diminished MEF2D transcriptional activity in Mef2d +/− retina is further reduced under photostimulation-induced oxidative stress. Reactive oxygen species cause an aberrant redox modification on MEF2D, consequently inhibiting transcription of its downstream target, nuclear factor (erythroid-derived 2)-like 2 (NRF2). NRF2 is a master regulator of phase II antiinflammatory and antioxidant gene expression. In the Mef2d heterozygous mouse retina, NRF2 is not up-regulated to a normal degree in the face of lightinduced oxidative stress, contributing to accelerated photoreceptor cell death. Furthermore, to combat this injury, we found that activation of the endogenous NRF2 pathway using proelectrophilic drugs rescues photoreceptors from photo-induced oxidative stress and may therefore represent a viable treatment for oxidative stress-induced photoreceptor degeneration, which is thought to contribute to some forms of retinitis pigmentosa and age-related macular degeneration.B lindness due to photoreceptor loss from a number of diseases is a prevalent and devastating condition in the human population. Genetic predisposition and environmental stress play major roles in the incidence and progression of the retinal degeneration. Understanding disease mechanisms and interactions of causative factors should help in the design of treatment strategies. Recent evidence indicates that oxidative stress, contributing to photoreceptor cell death, plays a significant role in the pathophysiology of nonsyndromic retinitis pigmentosa (RP) and possibly age-related macular degeneration (AMD) (1-3). Moreover, light-induced oxidative stress is known to potentiate photoreceptor loss in genetic models mimicking a number of human retinal degenerations (4-11).The oxidizing microenvironment of the retinal pigment epithelium (RPE)-photoreceptor complex has been predominantly attributed to high oxygen demand, abundant polyunsaturated fatty acids, and direct exposure to light, coupled with the adjacent choroidal hemodynamics (12). Light exposure compounded over many years in the presence of photosensitizers may prime photoreceptors and RPE for free radical/oxidative damage (12-14). In some animal models of photoreceptor degeneration, including RP and Leber congenital amaurosis, disease progression is accelerated by exposure to light and slowed by rearing in darkness (3, 15). Advanced age also compromises the endogenous antioxidant ...

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NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage

Cited by 230 publications

References 97 publications

Genetic rescue models refute nonautonomous rod cell death in retinitis pigmentosa

Genetic rescue models refute nonautonomous rod cell death in retinitis pigmentosa

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

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