Early Alterations of RNA Binding Protein (RBP) Homeostasis and ER Stress-Mediated Autophagy Contributes to Progressive Retinal Degeneration in the <i>rd10</i> Mouse Model of Retinitis Pigmentosa (RP)
The retinal degeneration 10 (<i>rd10</i>) mouse model is widely used to study retinitis pigmentosa (RP) pathomechanisms. It offers a rather unique opportunity to study trans-neuronal degeneration because the cell populations in question are separated anatomically and the mutated <i>...
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MDPI AG
2023-04-01
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| author | Alfred Yamoah Priyanka Tripathi Haihong Guo Leonie Scheve Peter Walter Sandra Johnen Frank Müller Joachim Weis Anand Goswami |
| author_facet | Alfred Yamoah Priyanka Tripathi Haihong Guo Leonie Scheve Peter Walter Sandra Johnen Frank Müller Joachim Weis Anand Goswami |
| author_sort | Alfred Yamoah |
| collection | DOAJ |
| description | The retinal degeneration 10 (<i>rd10</i>) mouse model is widely used to study retinitis pigmentosa (RP) pathomechanisms. It offers a rather unique opportunity to study trans-neuronal degeneration because the cell populations in question are separated anatomically and the mutated <i>Pde6b</i> gene is selectively expressed in rod photoreceptors. We hypothesized that RNA binding protein (RBP) aggregation and abnormal autophagy might serve as early pathogenic events, damaging non-photoreceptor retinal cell types that are not primarily targeted by the <i>Pde6b</i> gene defect. We used a combination of immunohistochemistry (DAB, immunofluorescence), electron microscopy (EM), subcellular fractionation, and Western blot analysis on the retinal preparations obtained from both <i>rd10</i> and wild-type mice. We found early, robust increases in levels of the protective endoplasmic reticulum (ER) calcium (Ca<sup>2+</sup>) buffering chaperone Sigma receptor 1 (SigR1) together with other ER-Ca<sup>2+</sup> buffering proteins in both photoreceptors and non-photoreceptor neuronal cells before any noticeable photoreceptor degeneration. In line with this, we found markedly altered expression of the autophagy proteins p62 and LC3, together with abnormal ER widening and large autophagic vacuoles as detected by EM. Interestingly, these changes were accompanied by early, prominent cytoplasmic and nuclear aggregation of the key RBPs including pTDP-43 and FET family RBPs and stress granule formation. We conclude that progressive neurodegeneration in the <i>rd10</i> mouse retina is associated with early disturbances of proteostasis and autophagy, along with abnormal cytoplasmic RBP aggregation. |
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| last_indexed | 2024-03-11T05:39:41Z |
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| spelling | doaj.art-43f65bd4a4144cb6b5183462d6a767082023-11-17T16:29:14ZengMDPI AGCells2073-44092023-04-01127109410.3390/cells12071094Early Alterations of RNA Binding Protein (RBP) Homeostasis and ER Stress-Mediated Autophagy Contributes to Progressive Retinal Degeneration in the <i>rd10</i> Mouse Model of Retinitis Pigmentosa (RP)Alfred Yamoah0Priyanka Tripathi1Haihong Guo2Leonie Scheve3Peter Walter4Sandra Johnen5Frank Müller6Joachim Weis7Anand Goswami8Institute of Neuropathology, University Hospital RWTH Aachen, 52074 Aachen, GermanyInstitute of Neuropathology, University Hospital RWTH Aachen, 52074 Aachen, GermanyInstitute of Neuropathology, University Hospital RWTH Aachen, 52074 Aachen, GermanyInstitute of Neuropathology, University Hospital RWTH Aachen, 52074 Aachen, GermanyDepartment of Ophthalmology, University Hospital RWTH Aachen, 52074 Aachen, GermanyDepartment of Ophthalmology, University Hospital RWTH Aachen, 52074 Aachen, GermanyInstitute of Biological Information Processing, Molecular and Cellular Physiology, IBI-1, Forschungszentrum Jülich GmbH, 52425 Jülich, GermanyInstitute of Neuropathology, University Hospital RWTH Aachen, 52074 Aachen, GermanyInstitute of Neuropathology, University Hospital RWTH Aachen, 52074 Aachen, GermanyThe retinal degeneration 10 (<i>rd10</i>) mouse model is widely used to study retinitis pigmentosa (RP) pathomechanisms. It offers a rather unique opportunity to study trans-neuronal degeneration because the cell populations in question are separated anatomically and the mutated <i>Pde6b</i> gene is selectively expressed in rod photoreceptors. We hypothesized that RNA binding protein (RBP) aggregation and abnormal autophagy might serve as early pathogenic events, damaging non-photoreceptor retinal cell types that are not primarily targeted by the <i>Pde6b</i> gene defect. We used a combination of immunohistochemistry (DAB, immunofluorescence), electron microscopy (EM), subcellular fractionation, and Western blot analysis on the retinal preparations obtained from both <i>rd10</i> and wild-type mice. We found early, robust increases in levels of the protective endoplasmic reticulum (ER) calcium (Ca<sup>2+</sup>) buffering chaperone Sigma receptor 1 (SigR1) together with other ER-Ca<sup>2+</sup> buffering proteins in both photoreceptors and non-photoreceptor neuronal cells before any noticeable photoreceptor degeneration. In line with this, we found markedly altered expression of the autophagy proteins p62 and LC3, together with abnormal ER widening and large autophagic vacuoles as detected by EM. Interestingly, these changes were accompanied by early, prominent cytoplasmic and nuclear aggregation of the key RBPs including pTDP-43 and FET family RBPs and stress granule formation. We conclude that progressive neurodegeneration in the <i>rd10</i> mouse retina is associated with early disturbances of proteostasis and autophagy, along with abnormal cytoplasmic RBP aggregation.https://www.mdpi.com/2073-4409/12/7/1094<i>rd10</i> retinaER-Ca<sup>2+</sup> homeostasisER chaperonesautophagyRBP aggregationneurodegeneration |
| spellingShingle | Alfred Yamoah Priyanka Tripathi Haihong Guo Leonie Scheve Peter Walter Sandra Johnen Frank Müller Joachim Weis Anand Goswami Early Alterations of RNA Binding Protein (RBP) Homeostasis and ER Stress-Mediated Autophagy Contributes to Progressive Retinal Degeneration in the <i>rd10</i> Mouse Model of Retinitis Pigmentosa (RP) Cells <i>rd10</i> retina ER-Ca<sup>2+</sup> homeostasis ER chaperones autophagy RBP aggregation neurodegeneration |
| title | Early Alterations of RNA Binding Protein (RBP) Homeostasis and ER Stress-Mediated Autophagy Contributes to Progressive Retinal Degeneration in the <i>rd10</i> Mouse Model of Retinitis Pigmentosa (RP) |
| title_full | Early Alterations of RNA Binding Protein (RBP) Homeostasis and ER Stress-Mediated Autophagy Contributes to Progressive Retinal Degeneration in the <i>rd10</i> Mouse Model of Retinitis Pigmentosa (RP) |
| title_fullStr | Early Alterations of RNA Binding Protein (RBP) Homeostasis and ER Stress-Mediated Autophagy Contributes to Progressive Retinal Degeneration in the <i>rd10</i> Mouse Model of Retinitis Pigmentosa (RP) |
| title_full_unstemmed | Early Alterations of RNA Binding Protein (RBP) Homeostasis and ER Stress-Mediated Autophagy Contributes to Progressive Retinal Degeneration in the <i>rd10</i> Mouse Model of Retinitis Pigmentosa (RP) |
| title_short | Early Alterations of RNA Binding Protein (RBP) Homeostasis and ER Stress-Mediated Autophagy Contributes to Progressive Retinal Degeneration in the <i>rd10</i> Mouse Model of Retinitis Pigmentosa (RP) |
| title_sort | early alterations of rna binding protein rbp homeostasis and er stress mediated autophagy contributes to progressive retinal degeneration in the i rd10 i mouse model of retinitis pigmentosa rp |
| topic | <i>rd10</i> retina ER-Ca<sup>2+</sup> homeostasis ER chaperones autophagy RBP aggregation neurodegeneration |
| url | https://www.mdpi.com/2073-4409/12/7/1094 |
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