Early Delivery of Misfolded PrP from ER to Lysosomes by Autophagy
Prion diseases are linked to the accumulation of a misfolded isoform (PrPSc) of prion protein (PrP). Evidence suggests that lysosomes are degradation endpoints and sites of the accumulation of PrPSc. We questioned whether lysosomes participate in the early quality control of newly generated misfol...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2013-01-01
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| Series: | International Journal of Cell Biology |
| Online Access: | http://dx.doi.org/10.1155/2013/560421 |
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| author | Constanza J. Cortes Kefeng Qin Eric M. Norstrom William N. Green Vytautas P. Bindokas James A. Mastrianni |
| author_facet | Constanza J. Cortes Kefeng Qin Eric M. Norstrom William N. Green Vytautas P. Bindokas James A. Mastrianni |
| author_sort | Constanza J. Cortes |
| collection | DOAJ |
| description | Prion diseases are linked to the accumulation of a misfolded isoform (PrPSc) of prion protein (PrP). Evidence suggests that lysosomes are degradation endpoints and sites of the accumulation of PrPSc. We questioned whether lysosomes participate in the early quality control of newly generated misfolded PrP. We found PrP carrying the disease-associated T182A mutation (Mut-PrP) was delivered to lysosomes in a Golgi-independent manner. Time-lapse live cell imaging revealed early formation and uptake of GFP-tagged Mut-PrP aggregates into LysoTracker labeled vesicles. Compared with Wt-PrP, Mut-PrP expression was associated with an elevation in several markers of the autophagy-lysosomal pathway, and it extensively colocalized with the autophagosome-specific marker, LC3B. In autophagy deficient (ATG5−/−) mouse embryonic fibroblasts, or in normal cells treated with the autophagy-inhibitor 3-MA, Mut-PrP colocalization with lysosomes was reduced to a similar extent. Additionally, 3-MA selectively impaired the degradation of insoluble Mut-PrP, resulting in an increase in protease-resistant PrP, whereas the induction of autophagy by rapamycin reduced it. These findings suggest that autophagy might function as a quality control mechanism to limit the accumulation of misfolded PrP that normally leads to the generation of PrPSc. |
| format | Article |
| id | doaj-art-cb8b29dc9e9b4a2eba2235bdfd02001d |
| institution | Kabale University |
| issn | 1687-8876 1687-8884 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | International Journal of Cell Biology |
| spelling | doaj-art-cb8b29dc9e9b4a2eba2235bdfd02001d2025-02-03T01:20:51ZengWileyInternational Journal of Cell Biology1687-88761687-88842013-01-01201310.1155/2013/560421560421Early Delivery of Misfolded PrP from ER to Lysosomes by AutophagyConstanza J. Cortes0Kefeng Qin1Eric M. Norstrom2William N. Green3Vytautas P. Bindokas4James A. Mastrianni5Departments of Neurology, MC2030, The University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, Chicago, IL 60637, USADepartments of Neurology, MC2030, The University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, Chicago, IL 60637, USADepartments of Neurology, MC2030, The University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, Chicago, IL 60637, USADepartments of Neurobiology, The University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USADepartments of Neurobiology, The University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USADepartments of Neurology, MC2030, The University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, Chicago, IL 60637, USAPrion diseases are linked to the accumulation of a misfolded isoform (PrPSc) of prion protein (PrP). Evidence suggests that lysosomes are degradation endpoints and sites of the accumulation of PrPSc. We questioned whether lysosomes participate in the early quality control of newly generated misfolded PrP. We found PrP carrying the disease-associated T182A mutation (Mut-PrP) was delivered to lysosomes in a Golgi-independent manner. Time-lapse live cell imaging revealed early formation and uptake of GFP-tagged Mut-PrP aggregates into LysoTracker labeled vesicles. Compared with Wt-PrP, Mut-PrP expression was associated with an elevation in several markers of the autophagy-lysosomal pathway, and it extensively colocalized with the autophagosome-specific marker, LC3B. In autophagy deficient (ATG5−/−) mouse embryonic fibroblasts, or in normal cells treated with the autophagy-inhibitor 3-MA, Mut-PrP colocalization with lysosomes was reduced to a similar extent. Additionally, 3-MA selectively impaired the degradation of insoluble Mut-PrP, resulting in an increase in protease-resistant PrP, whereas the induction of autophagy by rapamycin reduced it. These findings suggest that autophagy might function as a quality control mechanism to limit the accumulation of misfolded PrP that normally leads to the generation of PrPSc.http://dx.doi.org/10.1155/2013/560421 |
| spellingShingle | Constanza J. Cortes Kefeng Qin Eric M. Norstrom William N. Green Vytautas P. Bindokas James A. Mastrianni Early Delivery of Misfolded PrP from ER to Lysosomes by Autophagy International Journal of Cell Biology |
| title | Early Delivery of Misfolded PrP from ER to Lysosomes by Autophagy |
| title_full | Early Delivery of Misfolded PrP from ER to Lysosomes by Autophagy |
| title_fullStr | Early Delivery of Misfolded PrP from ER to Lysosomes by Autophagy |
| title_full_unstemmed | Early Delivery of Misfolded PrP from ER to Lysosomes by Autophagy |
| title_short | Early Delivery of Misfolded PrP from ER to Lysosomes by Autophagy |
| title_sort | early delivery of misfolded prp from er to lysosomes by autophagy |
| url | http://dx.doi.org/10.1155/2013/560421 |
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