Cargando…

Multidrug resistance protein 1 reduces the aggregation of mutant huntingtin in neuronal cells derived from the Huntington’s disease R6/2 model

Mutant huntingtin (mHtt) aggregation in the nucleus is the most readily apparent phenotype and cause of neuronal death in Huntington’s disease (HD). Inhibiting mHtt aggregation reduces cell death in the brain and is thus a promising therapeutic approach. The results of the present study demonstrated...

Descripción completa

Detalles Bibliográficos
Autores principales: Im, Wooseok, Ban, Jae-Jun, Chung, Jin-Young, Lee, Soon-Tae, Chu, Kon, Kim, Manho
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653614/
https://www.ncbi.nlm.nih.gov/pubmed/26586297
http://dx.doi.org/10.1038/srep16887
_version_ 1782401949789847552
author Im, Wooseok
Ban, Jae-Jun
Chung, Jin-Young
Lee, Soon-Tae
Chu, Kon
Kim, Manho
author_facet Im, Wooseok
Ban, Jae-Jun
Chung, Jin-Young
Lee, Soon-Tae
Chu, Kon
Kim, Manho
author_sort Im, Wooseok
collection PubMed
description Mutant huntingtin (mHtt) aggregation in the nucleus is the most readily apparent phenotype and cause of neuronal death in Huntington’s disease (HD). Inhibiting mHtt aggregation reduces cell death in the brain and is thus a promising therapeutic approach. The results of the present study demonstrated that mHtt aggregation in the nucleus was altered by the activity of multidrug resistance protein 1 (MDR1), which was experimentally modulated by verapamil, siRNA and an expression vector. MDR1 detoxifies drugs and metabolites through its excretory functions in the membrane compartment, thereby protecting cells against death or senescence. When they were treated with verapamil, R6/2 mice showed a progressive decline in rotarod performance and increased mHtt aggregation in the brain. Using neuronal stem cells from R6/2 mice, we developed an in vitro HD model to test mHtt accumulation in the nuclei of neurons. When MDR1 activity in cells was decreased by verapamil or siRNA, mHtt aggregation in the nuclei increased, whereas the induction of MDR1 resulted in a decrease in mHtt aggregation. Thus, our data provide evidence that MDR1 plays an important role in the clearance of mHtt aggregation and may thus be a potential target for improving the survival of neurons in Huntington’s disease.
format Online
Article
Text
id pubmed-4653614
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-46536142015-11-25 Multidrug resistance protein 1 reduces the aggregation of mutant huntingtin in neuronal cells derived from the Huntington’s disease R6/2 model Im, Wooseok Ban, Jae-Jun Chung, Jin-Young Lee, Soon-Tae Chu, Kon Kim, Manho Sci Rep Article Mutant huntingtin (mHtt) aggregation in the nucleus is the most readily apparent phenotype and cause of neuronal death in Huntington’s disease (HD). Inhibiting mHtt aggregation reduces cell death in the brain and is thus a promising therapeutic approach. The results of the present study demonstrated that mHtt aggregation in the nucleus was altered by the activity of multidrug resistance protein 1 (MDR1), which was experimentally modulated by verapamil, siRNA and an expression vector. MDR1 detoxifies drugs and metabolites through its excretory functions in the membrane compartment, thereby protecting cells against death or senescence. When they were treated with verapamil, R6/2 mice showed a progressive decline in rotarod performance and increased mHtt aggregation in the brain. Using neuronal stem cells from R6/2 mice, we developed an in vitro HD model to test mHtt accumulation in the nuclei of neurons. When MDR1 activity in cells was decreased by verapamil or siRNA, mHtt aggregation in the nuclei increased, whereas the induction of MDR1 resulted in a decrease in mHtt aggregation. Thus, our data provide evidence that MDR1 plays an important role in the clearance of mHtt aggregation and may thus be a potential target for improving the survival of neurons in Huntington’s disease. Nature Publishing Group 2015-11-20 /pmc/articles/PMC4653614/ /pubmed/26586297 http://dx.doi.org/10.1038/srep16887 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Im, Wooseok
Ban, Jae-Jun
Chung, Jin-Young
Lee, Soon-Tae
Chu, Kon
Kim, Manho
Multidrug resistance protein 1 reduces the aggregation of mutant huntingtin in neuronal cells derived from the Huntington’s disease R6/2 model
title Multidrug resistance protein 1 reduces the aggregation of mutant huntingtin in neuronal cells derived from the Huntington’s disease R6/2 model
title_full Multidrug resistance protein 1 reduces the aggregation of mutant huntingtin in neuronal cells derived from the Huntington’s disease R6/2 model
title_fullStr Multidrug resistance protein 1 reduces the aggregation of mutant huntingtin in neuronal cells derived from the Huntington’s disease R6/2 model
title_full_unstemmed Multidrug resistance protein 1 reduces the aggregation of mutant huntingtin in neuronal cells derived from the Huntington’s disease R6/2 model
title_short Multidrug resistance protein 1 reduces the aggregation of mutant huntingtin in neuronal cells derived from the Huntington’s disease R6/2 model
title_sort multidrug resistance protein 1 reduces the aggregation of mutant huntingtin in neuronal cells derived from the huntington’s disease r6/2 model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653614/
https://www.ncbi.nlm.nih.gov/pubmed/26586297
http://dx.doi.org/10.1038/srep16887
work_keys_str_mv AT imwooseok multidrugresistanceprotein1reducestheaggregationofmutanthuntingtininneuronalcellsderivedfromthehuntingtonsdiseaser62model
AT banjaejun multidrugresistanceprotein1reducestheaggregationofmutanthuntingtininneuronalcellsderivedfromthehuntingtonsdiseaser62model
AT chungjinyoung multidrugresistanceprotein1reducestheaggregationofmutanthuntingtininneuronalcellsderivedfromthehuntingtonsdiseaser62model
AT leesoontae multidrugresistanceprotein1reducestheaggregationofmutanthuntingtininneuronalcellsderivedfromthehuntingtonsdiseaser62model
AT chukon multidrugresistanceprotein1reducestheaggregationofmutanthuntingtininneuronalcellsderivedfromthehuntingtonsdiseaser62model
AT kimmanho multidrugresistanceprotein1reducestheaggregationofmutanthuntingtininneuronalcellsderivedfromthehuntingtonsdiseaser62model