Cargando…

microRNA dysregulation in polyglutamine toxicity of TATA-box binding protein is mediated through STAT1 in mouse neuronal cells

BACKGROUND: Polyglutamine diseases constitute a class of neurodegenerative disorders associated with expansion of the cytosine-adenine-guanine (CAG) triplet, in protein coding genes. Expansion of a polyglutamine tract in the N-terminal of TBP is the causal mutation in SCA17. Brain sections of patien...

Descripción completa

Detalles Bibliográficos
Autores principales: Roshan, Reema, Choudhary, Ashwani, Bhambri, Aksheev, Bakshi, Bhawani, Ghosh, Tanay, Pillai, Beena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543588/
https://www.ncbi.nlm.nih.gov/pubmed/28774347
http://dx.doi.org/10.1186/s12974-017-0925-3
_version_ 1783255174539640832
author Roshan, Reema
Choudhary, Ashwani
Bhambri, Aksheev
Bakshi, Bhawani
Ghosh, Tanay
Pillai, Beena
author_facet Roshan, Reema
Choudhary, Ashwani
Bhambri, Aksheev
Bakshi, Bhawani
Ghosh, Tanay
Pillai, Beena
author_sort Roshan, Reema
collection PubMed
description BACKGROUND: Polyglutamine diseases constitute a class of neurodegenerative disorders associated with expansion of the cytosine-adenine-guanine (CAG) triplet, in protein coding genes. Expansion of a polyglutamine tract in the N-terminal of TBP is the causal mutation in SCA17. Brain sections of patients with spinocerebellar ataxia 17 (SCA17), a type of neurodegenerative disease, have been reported to contain protein aggregates of TATA-binding protein (TBP). It is also implicated in other neurodegenerative diseases like Huntington’s disease, since the protein aggregates formed in such diseases also contain TBP. Dysregulation of miR-29a/b is another common feature of neurodegenerative diseases including Alzheimer’s disease, Huntington’s disease, and SCA17. Using a cellular model of SCA17, we identified key connections in the molecular pathway from protein aggregation to miRNA dysregulation. METHODS: Gene expression profiling was performed subsequent to the expression of TBP containing polyglutamine in a cellular model of SCA17. We studied the expression of STAT1 and other interferon-gamma dependent genes in neuronal apoptosis. The molecular pathway leading to the dysregulation of miRNA in response of protein aggregation and interferon release was investigated using RNAi-mediated knockdown of STAT1. RESULTS: We show that the accumulation of polyglutamine-TBP in the cells results in interferon-gamma release which in turn signals through STAT1 leading to downregulation of miR-29a/b. We propose that the release of interferons by cells harboring toxic protein aggregates may trigger a bystander effect resulting in loss of neurons. Interferon-gamma also led to upregulation of miR-322 although this effect is not mediated through STAT1. CONCLUSIONS: Our investigation shows that neuroinflammation could be an important player in mediating the transcriptional dysregulation of miRNA and the subsequent apoptotic effect of toxic polyglutamine-TBP. The involvement of immunomodulators in polyglutamine diseases holds special therapeutic relevance in the light of recent findings that interferon-gamma can modulate behavior.
format Online
Article
Text
id pubmed-5543588
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-55435882017-08-07 microRNA dysregulation in polyglutamine toxicity of TATA-box binding protein is mediated through STAT1 in mouse neuronal cells Roshan, Reema Choudhary, Ashwani Bhambri, Aksheev Bakshi, Bhawani Ghosh, Tanay Pillai, Beena J Neuroinflammation Research BACKGROUND: Polyglutamine diseases constitute a class of neurodegenerative disorders associated with expansion of the cytosine-adenine-guanine (CAG) triplet, in protein coding genes. Expansion of a polyglutamine tract in the N-terminal of TBP is the causal mutation in SCA17. Brain sections of patients with spinocerebellar ataxia 17 (SCA17), a type of neurodegenerative disease, have been reported to contain protein aggregates of TATA-binding protein (TBP). It is also implicated in other neurodegenerative diseases like Huntington’s disease, since the protein aggregates formed in such diseases also contain TBP. Dysregulation of miR-29a/b is another common feature of neurodegenerative diseases including Alzheimer’s disease, Huntington’s disease, and SCA17. Using a cellular model of SCA17, we identified key connections in the molecular pathway from protein aggregation to miRNA dysregulation. METHODS: Gene expression profiling was performed subsequent to the expression of TBP containing polyglutamine in a cellular model of SCA17. We studied the expression of STAT1 and other interferon-gamma dependent genes in neuronal apoptosis. The molecular pathway leading to the dysregulation of miRNA in response of protein aggregation and interferon release was investigated using RNAi-mediated knockdown of STAT1. RESULTS: We show that the accumulation of polyglutamine-TBP in the cells results in interferon-gamma release which in turn signals through STAT1 leading to downregulation of miR-29a/b. We propose that the release of interferons by cells harboring toxic protein aggregates may trigger a bystander effect resulting in loss of neurons. Interferon-gamma also led to upregulation of miR-322 although this effect is not mediated through STAT1. CONCLUSIONS: Our investigation shows that neuroinflammation could be an important player in mediating the transcriptional dysregulation of miRNA and the subsequent apoptotic effect of toxic polyglutamine-TBP. The involvement of immunomodulators in polyglutamine diseases holds special therapeutic relevance in the light of recent findings that interferon-gamma can modulate behavior. BioMed Central 2017-08-03 /pmc/articles/PMC5543588/ /pubmed/28774347 http://dx.doi.org/10.1186/s12974-017-0925-3 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Roshan, Reema
Choudhary, Ashwani
Bhambri, Aksheev
Bakshi, Bhawani
Ghosh, Tanay
Pillai, Beena
microRNA dysregulation in polyglutamine toxicity of TATA-box binding protein is mediated through STAT1 in mouse neuronal cells
title microRNA dysregulation in polyglutamine toxicity of TATA-box binding protein is mediated through STAT1 in mouse neuronal cells
title_full microRNA dysregulation in polyglutamine toxicity of TATA-box binding protein is mediated through STAT1 in mouse neuronal cells
title_fullStr microRNA dysregulation in polyglutamine toxicity of TATA-box binding protein is mediated through STAT1 in mouse neuronal cells
title_full_unstemmed microRNA dysregulation in polyglutamine toxicity of TATA-box binding protein is mediated through STAT1 in mouse neuronal cells
title_short microRNA dysregulation in polyglutamine toxicity of TATA-box binding protein is mediated through STAT1 in mouse neuronal cells
title_sort microrna dysregulation in polyglutamine toxicity of tata-box binding protein is mediated through stat1 in mouse neuronal cells
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543588/
https://www.ncbi.nlm.nih.gov/pubmed/28774347
http://dx.doi.org/10.1186/s12974-017-0925-3
work_keys_str_mv AT roshanreema micrornadysregulationinpolyglutaminetoxicityoftataboxbindingproteinismediatedthroughstat1inmouseneuronalcells
AT choudharyashwani micrornadysregulationinpolyglutaminetoxicityoftataboxbindingproteinismediatedthroughstat1inmouseneuronalcells
AT bhambriaksheev micrornadysregulationinpolyglutaminetoxicityoftataboxbindingproteinismediatedthroughstat1inmouseneuronalcells
AT bakshibhawani micrornadysregulationinpolyglutaminetoxicityoftataboxbindingproteinismediatedthroughstat1inmouseneuronalcells
AT ghoshtanay micrornadysregulationinpolyglutaminetoxicityoftataboxbindingproteinismediatedthroughstat1inmouseneuronalcells
AT pillaibeena micrornadysregulationinpolyglutaminetoxicityoftataboxbindingproteinismediatedthroughstat1inmouseneuronalcells