Endoplasmic reticulum stress in human photoreceptor diseases

Chan, Priscilla; Stolz, Julia; Kohl, Susanne; Chiang, Wei‐Chieh; Lin, Jonathan H.

doi:10.1016/j.brainres.2016.04.021

Cited by 44 publications

(29 citation statements)

References 42 publications

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“…The involvement of the ERS has been increasingly recognized as a contributor in a variety of diseases, including glaucoma [52], DR [53], AMD [54] and RP [55]. GRP78, a protein chaperone, was chosen as the ERS marker in the present experiment [56].…”

Section: Discussionmentioning

confidence: 99%

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

Yan

Long²,

Wei

et al. 2020

BMC Ophthalmol

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Background: Retinitis pigmentosa (RP) is a kind of inherited retinal degenerative diseases characterized by the progressive loss of photoreceptors. RP has been a conundrum without satisfactory countermeasures in clinic until now. Acetaldehyde dehydrogenase 2 (ALDH2), a major enzyme involved in aldehyde detoxification, has been demonstrated to be beneficial for a growing number of human diseases, such as cardiovascular dysfunction, diabetes mellitus and neurodegeneration. However, its protective effect against RP remains unknown. Our study explored the impact of ALDH2 on retinal function and structure in N-methyl-N-nitrosourea (MNU)-induced RP rats. Methods: Rats were gavaged with 5 mg/kg Alda-1, an ALDH2 agonist, 5 days before and 3 days after MNU administration. Assessments of retinal function and morphology as well as measurement of specific proteins expression level were conducted. Results: Electroretinogram recordings showed that Alda-1 administration alleviated the decrease in amplitude caused by MNU, rendering protection of retinal function. Mitigation of photoreceptor degeneration in MNU-treated retinas was observed by optical coherence tomography and retinal histological examination. In addition, Western blotting results revealed that ALDH2 protein expression level was upregulatedwith increased expression of SIRT1 protein after the Alda-1 intervention. Besides, endoplasmic reticulum stress (ERS) was reduced according to the significant downregulation of GRP78 protein, while apoptosis was ameliorated as shown by the decreased expression of PARP1 protein.Conclusions: Together, our data demonstrated that ALDH2 could provide preservation of retinal function and morphology against MNU-induced RP, with the underlying mechanism at least partly related to the modulation of SIRT1, ERS and apoptosis.

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Section: Discussionmentioning

confidence: 99%

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

Yan

Long²,

Wei

et al. 2020

BMC Ophthalmol

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“…Modulation of ER stress also protects injured neurons and improves functional recovery in experimental spinal cord injury, 44 , 45 stroke, 46 Alzheimer disease, 47 tauopathies, 48 Parkinson’s disease, 49 amyotrophic lateral sclerosis, 50 , 51 prion disease 52 , 53 , 54 and, most relevantly, retinal cell degenerations, including RGC 18 , 19 and photoreceptor. 12 , 16 , 55 , 56 Importantly, recent reports provide evidence of ER stress in brain and spinal cord lesions of human MS patients 24 and rodent EAE, 25 suggesting the importance of ER stress in the pathophysiology of MS. However, previous studies showed that PERK activation in oligodendrocytes promotes their survival in EAE, 39 , 57 and suggest that ER stress in oligodendrocytes is beneficial in demyelinating diseases.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection by eIF2α-CHOP inhibition and XBP-1 activation in EAE/optic neuritiss

et al. 2017

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No therapies exist to prevent neuronal deficits in multiple sclerosis (MS), because the molecular mechanism responsible for the progressive neurodegeneration is unknown. We previously showed that axon injury-induced neuronal endoplasmic reticulum (ER) stress plays an important role in retinal ganglion cell (RGC) death and optic nerve degeneration in traumatic and glaucomatous optic neuropathies. Optic neuritis, one of the most common clinical manifestations of MS, is readily modeled by experimental autoimmune encephalomyelitis (EAE) in mouse. Using this in vivo model, we now show that ER stress is induced early in EAE and that modulation of ER stress by inhibition of eIF2α-CHOP and activation of XBP-1 in RGC specifically, protects RGC somata and axons and preserves visual function. This finding adds to the evidence that ER stress is a general upstream mechanism for neurodegeneration and suggests that targeting ER stress molecules is a promising therapeutic strategy for neuroprotection in MS.

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“…11,21 Chronic ER stress induces cell death and thus may contribute to the cone dysfunction and vision loss observed in patients with ATF6 mutations. 22,23,16 Taking into account the fact that the overlapping clinical symptoms of different IRD procure choosing the proper genes for nucleotide sequence analysis, it seems reasonable to add the ATF6 gene to a list of so-called 'retinal genes' analysed by NGS methods.…”

Section: Discussionmentioning

confidence: 99%

Autosomal recessive cone-rod dystrophy can be caused by mutations in the ATF6 gene

et al. 2017

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Inherited retinal dystrophies (IRDs) are clinically and genetically highly heterogeneous, making clinical diagnosis difficult. The advances in high-throughput sequencing (ie, panel, exome and genome sequencing) have proven highly effective on defining the molecular basis of these disorders by identifying the underlying variants in the respective gene. Here we report two siblings affected by an IRD phenotype and a novel homozygous c.1691A>G (p.(Asp564Gly)) ATF6 (activating transcription factor 6A) missense substitution identified by whole exome sequencing analysis. The pathogenicity of the variant was confirmed by functional analyses done on patients' fibroblasts and on recombinant p.(Asp564Gly) protein. The ATF6 variant shows impaired production of the ATF6 cleaved transcriptional activator domain in response to endoplasmic reticulum stress. Detailed phenotypic examination revealed extinguished cone responses but also decreased rod responses together with the ability to discriminate some colours suggestive rather for cone-rod dystrophy than achromatopsia.

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Endoplasmic reticulum stress in human photoreceptor diseases

Cited by 44 publications

References 42 publications

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

Neuroprotection by eIF2α-CHOP inhibition and XBP-1 activation in EAE/optic neuritiss

Autosomal recessive cone-rod dystrophy can be caused by mutations in the ATF6 gene

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