Loss of PIKfyve drives the spongiform degeneration in prion diseases
Abstract Brain‐matter vacuolation is a defining trait of all prion diseases, yet its cause is unknown. Here, we report that prion infection and prion‐mimetic antibodies deplete the phosphoinositide kinase PIKfyve—which controls endolysosomal maturation—from mouse brains, cultured cells, organotypic...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2021-07-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202114714 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850119119369666560 |
|---|---|
| author | Asvin K K Lakkaraju Karl Frontzek Emina Lemes Uli Herrmann Marco Losa Rajlakshmi Marpakwar Adriano Aguzzi |
| author_facet | Asvin K K Lakkaraju Karl Frontzek Emina Lemes Uli Herrmann Marco Losa Rajlakshmi Marpakwar Adriano Aguzzi |
| author_sort | Asvin K K Lakkaraju |
| collection | DOAJ |
| description | Abstract Brain‐matter vacuolation is a defining trait of all prion diseases, yet its cause is unknown. Here, we report that prion infection and prion‐mimetic antibodies deplete the phosphoinositide kinase PIKfyve—which controls endolysosomal maturation—from mouse brains, cultured cells, organotypic brain slices, and brains of Creutzfeldt‐Jakob disease victims. We found that PIKfyve is acylated by the acyltransferases zDHHC9 and zDHHC21, whose juxtavesicular topology is disturbed by prion infection, resulting in PIKfyve deacylation and rapid degradation, as well as endolysosomal hypertrophy and activation of TFEB‐dependent lysosomal enzymes. A protracted unfolded protein response (UPR), typical of prion diseases, also induced PIKfyve deacylation and degradation. Conversely, UPR antagonists restored PIKfyve levels in prion‐infected cells. Overexpression of zDHHC9 and zDHHC21, administration of the antiprion polythiophene LIN5044, or supplementation with the PIKfyve reaction product PI(3,5)P2 suppressed prion‐induced vacuolation and restored lysosomal homeostasis. Thus, PIKfyve emerges as a central mediator of vacuolation and neurotoxicity in prion diseases. |
| format | Article |
| id | doaj-art-bf837fe83aa247b2b6e9fcd8e3b7e998 |
| institution | OA Journals |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-bf837fe83aa247b2b6e9fcd8e3b7e9982025-08-20T02:35:43ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-07-0113911710.15252/emmm.202114714Loss of PIKfyve drives the spongiform degeneration in prion diseasesAsvin K K Lakkaraju0Karl Frontzek1Emina Lemes2Uli Herrmann3Marco Losa4Rajlakshmi Marpakwar5Adriano Aguzzi6Institute of Neuropathology, University of ZurichInstitute of Neuropathology, University of ZurichInstitute of Neuropathology, University of ZurichInstitute of Neuropathology, University of ZurichInstitute of Neuropathology, University of ZurichInstitute of Neuropathology, University of ZurichInstitute of Neuropathology, University of ZurichAbstract Brain‐matter vacuolation is a defining trait of all prion diseases, yet its cause is unknown. Here, we report that prion infection and prion‐mimetic antibodies deplete the phosphoinositide kinase PIKfyve—which controls endolysosomal maturation—from mouse brains, cultured cells, organotypic brain slices, and brains of Creutzfeldt‐Jakob disease victims. We found that PIKfyve is acylated by the acyltransferases zDHHC9 and zDHHC21, whose juxtavesicular topology is disturbed by prion infection, resulting in PIKfyve deacylation and rapid degradation, as well as endolysosomal hypertrophy and activation of TFEB‐dependent lysosomal enzymes. A protracted unfolded protein response (UPR), typical of prion diseases, also induced PIKfyve deacylation and degradation. Conversely, UPR antagonists restored PIKfyve levels in prion‐infected cells. Overexpression of zDHHC9 and zDHHC21, administration of the antiprion polythiophene LIN5044, or supplementation with the PIKfyve reaction product PI(3,5)P2 suppressed prion‐induced vacuolation and restored lysosomal homeostasis. Thus, PIKfyve emerges as a central mediator of vacuolation and neurotoxicity in prion diseases.https://doi.org/10.15252/emmm.202114714neurodegenerationpalmitoylationprionspongiosisunfolded protein response |
| spellingShingle | Asvin K K Lakkaraju Karl Frontzek Emina Lemes Uli Herrmann Marco Losa Rajlakshmi Marpakwar Adriano Aguzzi Loss of PIKfyve drives the spongiform degeneration in prion diseases EMBO Molecular Medicine neurodegeneration palmitoylation prion spongiosis unfolded protein response |
| title | Loss of PIKfyve drives the spongiform degeneration in prion diseases |
| title_full | Loss of PIKfyve drives the spongiform degeneration in prion diseases |
| title_fullStr | Loss of PIKfyve drives the spongiform degeneration in prion diseases |
| title_full_unstemmed | Loss of PIKfyve drives the spongiform degeneration in prion diseases |
| title_short | Loss of PIKfyve drives the spongiform degeneration in prion diseases |
| title_sort | loss of pikfyve drives the spongiform degeneration in prion diseases |
| topic | neurodegeneration palmitoylation prion spongiosis unfolded protein response |
| url | https://doi.org/10.15252/emmm.202114714 |
| work_keys_str_mv | AT asvinkklakkaraju lossofpikfyvedrivesthespongiformdegenerationinpriondiseases AT karlfrontzek lossofpikfyvedrivesthespongiformdegenerationinpriondiseases AT eminalemes lossofpikfyvedrivesthespongiformdegenerationinpriondiseases AT uliherrmann lossofpikfyvedrivesthespongiformdegenerationinpriondiseases AT marcolosa lossofpikfyvedrivesthespongiformdegenerationinpriondiseases AT rajlakshmimarpakwar lossofpikfyvedrivesthespongiformdegenerationinpriondiseases AT adrianoaguzzi lossofpikfyvedrivesthespongiformdegenerationinpriondiseases |