The interaction between RE1-silencing transcription factor (REST) and heat shock protein 90 as new therapeutic target against Huntington’s disease.

The interaction between RE1-silencing transcription factor (REST) and heat shock protein 90 as new therapeutic target against Huntington’s disease.

Publication date: Mar 16, 2019

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.

Open Access PDF

Orozco-D’iaz, R., S’anchez-‘Alvarez, A., Hern’andez-Hern’andez, J.M., and Tapia-Ram’irez, J. The interaction between RE1-silencing transcription factor (REST) and heat shock protein 90 as new therapeutic target against Huntington’s disease. 06597. 2019 PLoS One (14):7.

Concepts Keywords
Antisense Oligonucleotide Hsp90
BDNF Branches of biology
Cytotoxicity Degenerative disease
Degenerative Disease RE1-silencing transcription factor
Endogenous Heat shock response
Gene Brain-derived neurotrophic factor
Heat Shock Huntington’s disease
Hsp90 Huntingtin
Huntingtin
Huntington
Hybrid
Mutant
N Terminus
Neurons
Neuroprotective
Nucleus
Progressive
REST
Striatal
Transcription Factor
Yeast

Semantics

Type Source Name
gene UNIPROT PDGFB
gene UNIPROT TRIM28
gene UNIPROT DEPP1
gene UNIPROT GOPC
drug DRUGBANK Coenzyme M
gene UNIPROT NOVA2
pathway BSID Axon guidance
drug DRUGBANK Gelatin
gene UNIPROT SLC35G1
gene UNIPROT DESI1
gene UNIPROT KIT
gene UNIPROT RAB35
drug DRUGBANK Hyaluronic acid
gene UNIPROT GAPDH
gene UNIPROT PARP1
gene UNIPROT MBOAT4
gene UNIPROT CD36
gene UNIPROT FAT1
disease MESH separated
gene UNIPROT GKN2
gene UNIPROT ERVK-21
gene UNIPROT ERVK-18
gene UNIPROT HERV-K104
gene UNIPROT ERVK-10
gene UNIPROT HERVK_113
gene UNIPROT ERVK-19
gene UNIPROT ERVK-25
gene UNIPROT ERVK-24
gene UNIPROT ERVK-8
gene UNIPROT ERVK-6
gene UNIPROT ERVK-7
gene UNIPROT ERVK-9
drug DRUGBANK Sucrose
drug DRUGBANK Potassium Chloride
gene UNIPROT PRDM10
drug DRUGBANK Tromethamine
drug DRUGBANK L-Phenylalanine
drug DRUGBANK Edetic Acid
gene UNIPROT SDS
drug DRUGBANK Sodium lauryl sulfate
drug DRUGBANK Glycerin
drug DRUGBANK Urea
gene UNIPROT CES2
gene UNIPROT CASP1
gene UNIPROT TUBE1
drug DRUGBANK Imidazole
gene UNIPROT GAL
gene UNIPROT GCSAM
drug DRUGBANK L-Leucine
gene UNIPROT TBPL1
gene UNIPROT TYRP1
drug DRUGBANK L-Tryptophan
gene UNIPROT PYURF
gene UNIPROT ENO2
gene UNIPROT TNFSF14
gene UNIPROT MENT
drug DRUGBANK Trestolone
drug DRUGBANK Tretinoin
drug DRUGBANK Streptomycin
drug DRUGBANK L-Glutamine
drug DRUGBANK Amino acids
gene UNIPROT FBXO8
gene UNIPROT FBRS
drug DRUGBANK Geldanamycin
pathway BSID Apoptosis
gene UNIPROT SNAP25
pathway BSID Proteasome
gene UNIPROT CLU
gene UNIPROT CARD8
gene UNIPROT HIP1
gene UNIPROT IFT57
gene UNIPROT SP1
gene UNIPROT DAND5
gene UNIPROT APEX1
gene UNIPROT HAP1
gene UNIPROT PRICKLE1
gene UNIPROT RILP
pathway BSID Neurodegenerative Diseases
disease MESH epileptic seizures
disease MESH hypoxia
disease MESH growth
pathway BSID Oxidative Stress
disease MESH oxidative stress
gene UNIPROT MST1R
gene UNIPROT ERBB2
pathway BSID Brain derived neurotrophic factor
gene UNIPROT SLC6A4
disease MESH neurodegenerative disorder
gene UNIPROT KNTC1
gene UNIPROT CEL
drug DRUGBANK Angelica archangelica root
gene UNIPROT DAZ1
disease DOID Huntington disease
disease MESH Huntington disease
disease MESH death
disease MESH repression
disease DOID degenerative disease
gene UNIPROT BDNF
gene UNIPROT HTT
disease MESH shock
gene UNIPROT REST

Original Article

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