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The interaction between RE1-silencing transcription factor (REST) and heat shock protein 90 as new therapeutic target against Huntington's disease
- Source :
- PLoS ONE, Vol 14, Iss 7, p e0220393 (2019), PLoS ONE
- Publication Year :
- 2019
- Publisher :
- Public Library of Science (PLoS), 2019.
-
Abstract
- The wild type huntingtin protein (Htt), supports the production of brain-derived neurotrophic factor (BDNF), a survival factor for striatal neurons, through cytoplasmic sequestering of RE-1silencing transcription factor (REST). In Huntington´s Disease an inherited degenerative disease, caused by a CAG expansion in the 5´coding region of the gene, the mutant huntingtin protein (mHtt), causes that REST enters pathologically into the nucleus of cells, resulting in the repression of neuronal genes including BDNF, resulting in the progressive neuronal death. It has been reported that Htt associates with Hsp90 and this interaction is involved in regulation of huntingtin aggregation. Discovering mechanisms to reduce the cellular levels of mutant huntingtin and REST provide promising strategies for treating Huntington disease. Here, we use the yeast two-hybrid system to show that N-terminus or REST interacts with the heat shock protein 90 (Hsp90) and identifies REST as an Hsp90 Client Protein. To assess the effects of Hsp90 we used antisense oligonucleotide, and evaluated the levels mHtt and REST levels. Our results show that direct knockdown of endogenous Hsp90 significantly reduces the levels of REST and mutant Huntingtin, decreased the percentage of cells with mHtt in nucleus and rescued cells from mHtt-induced cellular cytotoxicity. Additionally Hsp90-specific inhibitors geldanamicyn and PUH71 dramatically reduced mHtt and REST levels, thereby providing neuroprotective activity. Our data show that Hsp90 is necessary to maintain the levels of REST and mHtt, which suggests that the interactions between Hsp90-REST and Hsp90-Huntingtin could be potential therapeutic targets in Huntington's disease.
- Subjects :
- 0301 basic medicine
Cytoplasm
Huntingtin
Gene Expression
Apoptosis
RE1-silencing transcription factor
Biochemistry
0302 clinical medicine
Neurotrophic factors
Animal Cells
Medicine and Health Sciences
Benzoquinones
Neurons
Gene knockdown
Neuronal Death
Huntingtin Protein
Multidisciplinary
biology
Cell Death
Cell Differentiation
Neurodegenerative Diseases
Cell biology
Precipitation Techniques
Huntington Disease
Neurology
Cell Processes
Genetic Diseases
Gene Knockdown Techniques
Medicine
Cellular Types
Neuronal Differentiation
Research Article
Protein Binding
congenital, hereditary, and neonatal diseases and abnormalities
Lactams, Macrocyclic
Science
Research and Analysis Methods
Models, Biological
Cell Line
03 medical and health sciences
Huntington's disease
Heat shock protein
DNA-binding proteins
mental disorders
medicine
Genetics
Immunoprecipitation
Humans
Gene Regulation
HSP90 Heat-Shock Proteins
Transcription factor
Clinical Genetics
Cell Nucleus
Binding Sites
Autosomal Dominant Diseases
Biology and Life Sciences
Proteins
Cell Biology
medicine.disease
Regulatory Proteins
nervous system diseases
Repressor Proteins
030104 developmental biology
nervous system
Cellular Neuroscience
Mutation
biology.protein
030217 neurology & neurosurgery
Developmental Biology
Neuroscience
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 14
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....df60edf46e2b3cfa4a88ea72c2e5d941