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Inhibition of Autophagy Flux Promotes Secretion of Chondroitin Sulfate Proteoglycans in Primary Rat Astrocytes

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Abstract

Following spinal cord injury (SCI), reactive astrocytes in the glial scar produce high levels of chondroitin sulfate proteoglycans (CSPGs), which are known to inhibit axonal regeneration. Transforming growth factor beta (TGFβ) is a well-known factor that induces the production of CSPGs, and in this study, we report a novel mechanism underlying TGFβ’s effects on CSPG secretion in primary rat astrocytes. We observed increased TGFβ-induced secretion of the CSPGs neurocan and brevican, and this occurred simultaneously with inhibition of autophagy flux. In addition, we show that neurocan and brevican levels are further increased when TGFβ is administered in the presence of an autophagy inhibitor, Bafilomycin-A1, while they are reduced when cells are treated with a concentration of rapamycin that is not sufficient to induce autophagy. These findings suggest that TGFβ mediates its effects on CSPG secretion through autophagy pathways. They also represent a potential new approach to reduce CSPG secretion in vivo by targeting autophagy pathways, which could improve axonal regeneration after SCI.

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Fig. 1
Fig. 2

© Red DND-99 and the cells were then fixed and immunostained for LC3-β. TGFβ induced lysosomal acidification as demonstrated by an increase in LysoTracker© Red DND-99 staining, and accumulation of LC3β puncta (arrows), but they did not co-localize. Bafilomycin-A1 and chloroquine in the presence of TGFβ increased accumulation of LC3β puncta and its dissociation with lysosomes (p < 0.0001). Rapamycin had no effect on LC3β puncta, while decreasing lysosomal acidification. Graph depicts average numbers of LC3β-positive puncta ± SEM (*p < 0.05, ***p < 0.001, ****p < 0.0001; ns, not significant). Immunocytochemistry was performed in three independent biological replicates. Scale bar = 20 µm

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Acknowledgements

JA was supported by Vanier Canada Graduate Scholarship (Vanier CGS) funded by the Canadian Institute of Health Research (CIHR). SG was supported by a Research Manitoba New Operating grant. MMK and VDS were the recipients of an Undergraduate Research Award (Office of the Vice-President – Research and International, University of Manitoba). SSH was supported by operating grants from the Natural Sciences and Engineering Research Council of Canada (Discovery Grant), the Manitoba Spinal Cord Injury Research Committee (Canadian Paraplegic Association), and the Wings for Life Spinal Cord Research Foundation. The authors thank Mrs. Dana Henderson, Mrs. Farhana Begum, and the staff of the Human Anatomy and Cell Science core histology facility for preparing and sectioning the blocks for the electron microscopy experiments.

Funding

This research was supported by operating grants from Research Manitoba and CancerCare Manitoba Foundation (SG), the Natural Sciences and Engineering Research Council of Canada (SSH), the Manitoba Spinal Cord Injury Research Committee (Canadian Paraplegic Association – SSH), and the Wings for Life Spinal Cord Research Foundation (SSH).

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  1. Department of Human Anatomy and Cell Science, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, MB, R3E 0J9, Canada

    Javad Alizadeh, Matthew M. Kochan, Vanessa D. Stewart, Dennis A. Drewnik, Sari S. Hannila & Saeid Ghavami

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  1. Javad Alizadeh
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MMK and DAD performed Western blotting and immunocytochemistry experiments. VDS performed Western blotting experiments, prepared figures, and wrote the manuscript. JA prepared the manuscript and graphical abstract. SG designed experiments, performed electron microscopy, prepared figures, and finalized the manuscript. SSH supervised all experiments, performed cell culture and prepared samples, prepared figures, and wrote the manuscript.

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Correspondence to Sari S. Hannila or Saeid Ghavami.

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Alizadeh, J., Kochan, M.M., Stewart, V.D. et al. Inhibition of Autophagy Flux Promotes Secretion of Chondroitin Sulfate Proteoglycans in Primary Rat Astrocytes. Mol Neurobiol 58, 6077–6091 (2021). https://doi.org/10.1007/s12035-021-02533-4

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  • DOI: https://doi.org/10.1007/s12035-021-02533-4

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