Cargando…
Control of Alzheimer's Amyloid Beta Toxicity by the High Molecular Weight Immunophilin FKBP52 and Copper Homeostasis in Drosophila
FK506 binding proteins (FKBPs), also called immunophilins, are prolyl-isomerases (PPIases) that participate in a wide variety of cellular functions including hormone signaling and protein folding. Recent studies indicate that proteins that contain PPIase activity can also alter the processing of Alz...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2010
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801609/ https://www.ncbi.nlm.nih.gov/pubmed/20084280 http://dx.doi.org/10.1371/journal.pone.0008626 |
_version_ | 1782175941001216000 |
---|---|
author | Sanokawa-Akakura, Reiko Cao, Weihuan Allan, Kirsten Patel, Khyati Ganesh, Anupama Heiman, Gary Burke, Richard Kemp, Francis W. Bogden, John D. Camakaris, James Birge, Raymond B. Konsolaki, Mary |
author_facet | Sanokawa-Akakura, Reiko Cao, Weihuan Allan, Kirsten Patel, Khyati Ganesh, Anupama Heiman, Gary Burke, Richard Kemp, Francis W. Bogden, John D. Camakaris, James Birge, Raymond B. Konsolaki, Mary |
author_sort | Sanokawa-Akakura, Reiko |
collection | PubMed |
description | FK506 binding proteins (FKBPs), also called immunophilins, are prolyl-isomerases (PPIases) that participate in a wide variety of cellular functions including hormone signaling and protein folding. Recent studies indicate that proteins that contain PPIase activity can also alter the processing of Alzheimer's Amyloid Precursor Protein (APP). Originally identified in hematopoietic cells, FKBP52 is much more abundantly expressed in neurons, including the hippocampus, frontal cortex, and basal ganglia. Given the fact that the high molecular weight immunophilin FKBP52 is highly expressed in CNS regions susceptible to Alzheimer's, we investigated its role in Aβ toxicity. Towards this goal, we generated Aβ transgenic Drosophila that harbor gain of function or loss of function mutations of FKBP52. FKBP52 overexpression reduced the toxicity of Aβ and increased lifespan in Aβ flies, whereas loss of function of FKBP52 exacerbated these Aβ phenotypes. Interestingly, the Aβ pathology was enhanced by mutations in the copper transporters Atox1, which interacts with FKBP52, and Ctr1A and was suppressed in FKBP52 mutant flies raised on a copper chelator diet. Using mammalian cultures, we show that FKBP52 (−/−) cells have increased intracellular copper and higher levels of Aβ. This effect is reversed by reconstitution of FKBP52. Finally, we also found that FKBP52 formed stable complexes with APP through its FK506 interacting domain. Taken together, these studies identify a novel role for FKBP52 in modulating toxicity of Aβ peptides. |
format | Text |
id | pubmed-2801609 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-28016092010-01-16 Control of Alzheimer's Amyloid Beta Toxicity by the High Molecular Weight Immunophilin FKBP52 and Copper Homeostasis in Drosophila Sanokawa-Akakura, Reiko Cao, Weihuan Allan, Kirsten Patel, Khyati Ganesh, Anupama Heiman, Gary Burke, Richard Kemp, Francis W. Bogden, John D. Camakaris, James Birge, Raymond B. Konsolaki, Mary PLoS One Research Article FK506 binding proteins (FKBPs), also called immunophilins, are prolyl-isomerases (PPIases) that participate in a wide variety of cellular functions including hormone signaling and protein folding. Recent studies indicate that proteins that contain PPIase activity can also alter the processing of Alzheimer's Amyloid Precursor Protein (APP). Originally identified in hematopoietic cells, FKBP52 is much more abundantly expressed in neurons, including the hippocampus, frontal cortex, and basal ganglia. Given the fact that the high molecular weight immunophilin FKBP52 is highly expressed in CNS regions susceptible to Alzheimer's, we investigated its role in Aβ toxicity. Towards this goal, we generated Aβ transgenic Drosophila that harbor gain of function or loss of function mutations of FKBP52. FKBP52 overexpression reduced the toxicity of Aβ and increased lifespan in Aβ flies, whereas loss of function of FKBP52 exacerbated these Aβ phenotypes. Interestingly, the Aβ pathology was enhanced by mutations in the copper transporters Atox1, which interacts with FKBP52, and Ctr1A and was suppressed in FKBP52 mutant flies raised on a copper chelator diet. Using mammalian cultures, we show that FKBP52 (−/−) cells have increased intracellular copper and higher levels of Aβ. This effect is reversed by reconstitution of FKBP52. Finally, we also found that FKBP52 formed stable complexes with APP through its FK506 interacting domain. Taken together, these studies identify a novel role for FKBP52 in modulating toxicity of Aβ peptides. Public Library of Science 2010-01-13 /pmc/articles/PMC2801609/ /pubmed/20084280 http://dx.doi.org/10.1371/journal.pone.0008626 Text en Sanokawa-Akakura et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Sanokawa-Akakura, Reiko Cao, Weihuan Allan, Kirsten Patel, Khyati Ganesh, Anupama Heiman, Gary Burke, Richard Kemp, Francis W. Bogden, John D. Camakaris, James Birge, Raymond B. Konsolaki, Mary Control of Alzheimer's Amyloid Beta Toxicity by the High Molecular Weight Immunophilin FKBP52 and Copper Homeostasis in Drosophila |
title | Control of Alzheimer's Amyloid Beta Toxicity by the High Molecular Weight Immunophilin FKBP52 and Copper Homeostasis in Drosophila
|
title_full | Control of Alzheimer's Amyloid Beta Toxicity by the High Molecular Weight Immunophilin FKBP52 and Copper Homeostasis in Drosophila
|
title_fullStr | Control of Alzheimer's Amyloid Beta Toxicity by the High Molecular Weight Immunophilin FKBP52 and Copper Homeostasis in Drosophila
|
title_full_unstemmed | Control of Alzheimer's Amyloid Beta Toxicity by the High Molecular Weight Immunophilin FKBP52 and Copper Homeostasis in Drosophila
|
title_short | Control of Alzheimer's Amyloid Beta Toxicity by the High Molecular Weight Immunophilin FKBP52 and Copper Homeostasis in Drosophila
|
title_sort | control of alzheimer's amyloid beta toxicity by the high molecular weight immunophilin fkbp52 and copper homeostasis in drosophila |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801609/ https://www.ncbi.nlm.nih.gov/pubmed/20084280 http://dx.doi.org/10.1371/journal.pone.0008626 |
work_keys_str_mv | AT sanokawaakakurareiko controlofalzheimersamyloidbetatoxicitybythehighmolecularweightimmunophilinfkbp52andcopperhomeostasisindrosophila AT caoweihuan controlofalzheimersamyloidbetatoxicitybythehighmolecularweightimmunophilinfkbp52andcopperhomeostasisindrosophila AT allankirsten controlofalzheimersamyloidbetatoxicitybythehighmolecularweightimmunophilinfkbp52andcopperhomeostasisindrosophila AT patelkhyati controlofalzheimersamyloidbetatoxicitybythehighmolecularweightimmunophilinfkbp52andcopperhomeostasisindrosophila AT ganeshanupama controlofalzheimersamyloidbetatoxicitybythehighmolecularweightimmunophilinfkbp52andcopperhomeostasisindrosophila AT heimangary controlofalzheimersamyloidbetatoxicitybythehighmolecularweightimmunophilinfkbp52andcopperhomeostasisindrosophila AT burkerichard controlofalzheimersamyloidbetatoxicitybythehighmolecularweightimmunophilinfkbp52andcopperhomeostasisindrosophila AT kempfrancisw controlofalzheimersamyloidbetatoxicitybythehighmolecularweightimmunophilinfkbp52andcopperhomeostasisindrosophila AT bogdenjohnd controlofalzheimersamyloidbetatoxicitybythehighmolecularweightimmunophilinfkbp52andcopperhomeostasisindrosophila AT camakarisjames controlofalzheimersamyloidbetatoxicitybythehighmolecularweightimmunophilinfkbp52andcopperhomeostasisindrosophila AT birgeraymondb controlofalzheimersamyloidbetatoxicitybythehighmolecularweightimmunophilinfkbp52andcopperhomeostasisindrosophila AT konsolakimary controlofalzheimersamyloidbetatoxicitybythehighmolecularweightimmunophilinfkbp52andcopperhomeostasisindrosophila |