Artikel
Altered autophagy and RNA binding proteins (RBPs) together with ER chaperones are linked to retinal degeneration in the rd10 mouse model of retinitis pigmentosa
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Autoren
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Alfred Yamoah
- Institute of Neuropathology RWTH Aachen University Medical School Aachen/D
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H. Guo
- Institute of Neuropathology RWTH Aachen University Medical School Aachen/D
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P. Tripathi
- Institute of Neuropathology RWTH Aachen University Medical School Aachen/D
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I. Katona
- Institute of Neuropathology RWTH Aachen University Medical School Aachen/D
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P. Walter
- Department of Ophthalmology RWTH Aachen University Medical School Aachen/D
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S. Johnen
- Department of Ophthalmology RWTH Aachen University Medical School Aachen/D
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F. Müller
- Institute of Complex Systems Cellular Biophysics ICS-4 Forschungszentrum Jülich GmbH Juelich/D
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A. Goswami
- Institute of Neuropathology RWTH Aachen University Medical School Aachen/D
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J. Weis
- Institute of Neuropathology RWTH Aachen University Medical School Aachen/D
| Veröffentlicht: | 10. Dezember 2019 |
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Gliederung
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Background: Autosomal recessive retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease with no effective treatment available so far. The mouse line rd10 displaying a progressive photoreceptor degeneration based on a mutation in the gene coding for rod Pde6b serves as a valuable model for RP.
Objective: Autophagy and RBPs alterations are major pathomechanisms in many neurodegenerative disorders. The current study was designed to understand the involvement of autophagy and RBPs homeostasis in rd10 mice and to elucidate the neuroprotective effects of endoplasmic reticulum (ER) chaperones.
Methods: We used a wide range of neuropathological techniques including routine histology, immunohistochemistry, confocal microscopy complemented with electron microscopy and biochemical techniques such as Western blotting and sub-cellular fractionation on rd10 mouse retina samples.
Results: In rd10 mice at postnatal day 25 (P25), when photoreceptor degeneration is pronounced, photoreceptors displayed increased immunoreactivity for the unfolded protein response (UPR) marker pPERK together with a robust increase in the ER chaperones GRP78/Bip and Sigma receptor 1 (SigR1), suggesting acute ER stress in the affected cells. Consistent with the notion of ER stress-induced autophagy, we observed elevated levels of autophagy markers such as p62, LC3 and Lamp2 in the rd10 several retinal cell layers compared to the age matched controls. Autophagy pathways are linked to RBP homeostasis. Consistent with this we observed cytoplasmic mis-localization and aggregation of the key RBPs pTDP-43, FUS, and matrin 3. In many instances, pTDP43 aggregates were co-localized with aggregates of matrin 3.
Conclusion: Our results suggest that 1) neuroprotective ER chaperones are upregulated in degenerating photoreceptors that are still present at P25 and 2) that cytoplasmic mis-localization of key RBPs known to be crucial in neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is involved in retinal degeneration in the rd10 mouse model of RP.
Support: The study was supported by the DFG grants MU-3036/3-3, WA-1472/6-3, JO-1263/1-3, and WE1406/14-3 and by the Interdisciplinary Centre for Clinical Research (IZKF Aachen, N7-4), EU Joint Program Neurodegenerative Disease Research (JPND)
