Early Alterations of RNA Binding Protein (RBP) Homeostasis and ER Stress-Mediated Autophagy Contributes to Progressive Retinal Degeneration in the rd10 Mouse Model of Retinitis Pigmentosa (RP)

Alfred Yamoah; Priyanka Tripathi; Haihong Guo; Leonie Scheve; Peter Walter; Sandra Johnen; Frank Müller; Joachim Weis; Anand Goswami

doi:10.3390/cells12071094

Early Alterations of RNA Binding Protein (RBP) Homeostasis and ER Stress-Mediated Autophagy Contributes to Progressive Retinal Degeneration in the rd10 Mouse Model of Retinitis Pigmentosa (RP)

Cells. 2023 Apr 6;12(7):1094. doi: 10.3390/cells12071094.

Authors

Alfred Yamoah^{1

2}, Priyanka Tripathi^{1

2}, Haihong Guo¹, Leonie Scheve¹, Peter Walter³, Sandra Johnen³, Frank Müller⁴, Joachim Weis¹, Anand Goswami^{1

5

6}

Affiliations

¹ Institute of Neuropathology, University Hospital RWTH Aachen, 52074 Aachen, Germany.
² EURON-European Graduate School of Neuroscience, Maastricht University, 6229 ER Maastricht, The Netherlands.
³ Department of Ophthalmology, University Hospital RWTH Aachen, 52074 Aachen, Germany.
⁴ Institute of Biological Information Processing, Molecular and Cellular Physiology, IBI-1, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany.
⁵ Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
⁶ Department of Neurology, Eleanor and Lou Gehrig ALS Center, Columbia University, New York, NY 10032, USA.

Abstract

The retinal degeneration 10 (rd10) 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 Pde6b 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 Pde6b 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 rd10 and wild-type mice. We found early, robust increases in levels of the protective endoplasmic reticulum (ER) calcium (Ca²⁺) buffering chaperone Sigma receptor 1 (SigR1) together with other ER-Ca²⁺ 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 rd10 mouse retina is associated with early disturbances of proteostasis and autophagy, along with abnormal cytoplasmic RBP aggregation.

Keywords: ER chaperones; ER-Ca2+ homeostasis; RBP aggregation; autophagy; neurodegeneration; rd10 retina.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy
Homeostasis
Mice
RNA-Binding Proteins
Retinal Degeneration* / pathology
Retinitis Pigmentosa* / genetics

Substances

RNA-Binding Proteins

Grants and funding

This research was supported by the DFG grants, WE1406/14-3 to J.W., WE 1406/16-1 to J.W. and A.G., MU-3036/3-3 to F.M., WA-1472/6-3 to P.W., and JO-1263/1-3 to S.J., by the Interdisciplinary Centre for Clinical Research (IZKF Aachen, N7-4, to A.G. and J.W.) and by the EU Joint Program Neurodegenerative Disease Research (JPND, Fly-SMALS, to J.W.).