Cargando…
Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients
A hexanucleotide (GGGGCC) repeat expansion in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Reduced expression of the C9ORF72 gene product has been proposed as a potential contributor to disease pathogenesis. Addit...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031111/ https://www.ncbi.nlm.nih.gov/pubmed/29973287 http://dx.doi.org/10.1186/s40478-018-0555-8 |
_version_ | 1783337255976304640 |
---|---|
author | Mordes, Daniel A. Prudencio, Mercedes Goodman, Lindsey D. Klim, Joseph R. Moccia, Rob Limone, Francesco Pietilainen, Olli Chowdhary, Kaitavjeet Dickson, Dennis W. Rademakers, Rosa Bonini, Nancy M. Petrucelli, Leonard Eggan, Kevin |
author_facet | Mordes, Daniel A. Prudencio, Mercedes Goodman, Lindsey D. Klim, Joseph R. Moccia, Rob Limone, Francesco Pietilainen, Olli Chowdhary, Kaitavjeet Dickson, Dennis W. Rademakers, Rosa Bonini, Nancy M. Petrucelli, Leonard Eggan, Kevin |
author_sort | Mordes, Daniel A. |
collection | PubMed |
description | A hexanucleotide (GGGGCC) repeat expansion in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Reduced expression of the C9ORF72 gene product has been proposed as a potential contributor to disease pathogenesis. Additionally, repetitive RNAs and dipeptide repeat proteins (DPRs), such as poly-GR, can be produced by this hexanucleotide expansion that disrupt a number of cellular processes, potentially contributing to neural degeneration. To better discern which of these mechanisms leads to disease-associated changes in patient brains, we analyzed gene expression data generated from the cortex and cerebellum. We found that transcripts encoding heat shock proteins (HSPs) regulated by the HSF1 transcription factor were significantly induced in C9ORF72-ALS/FTLD patients relative to both sporadic ALS/FTLD cases and controls. Treatment of human neurons with chemically synthesized DPRs was sufficient to activate a similar transcriptional response. Expression of GGGGCC repeats and also poly-GR in the brains of Drosophila lead to the upregulation of HSF1 and the same highly-conserved HSPs. Additionally, HSF1 was a modifier of poly-GR toxicity in Drosophila. Our results suggest that the expression of DPRs are associated with upregulation of HSF1 and activation of a heat shock response in C9ORF72-ALS/FTLD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-018-0555-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6031111 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-60311112018-07-11 Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients Mordes, Daniel A. Prudencio, Mercedes Goodman, Lindsey D. Klim, Joseph R. Moccia, Rob Limone, Francesco Pietilainen, Olli Chowdhary, Kaitavjeet Dickson, Dennis W. Rademakers, Rosa Bonini, Nancy M. Petrucelli, Leonard Eggan, Kevin Acta Neuropathol Commun Research A hexanucleotide (GGGGCC) repeat expansion in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Reduced expression of the C9ORF72 gene product has been proposed as a potential contributor to disease pathogenesis. Additionally, repetitive RNAs and dipeptide repeat proteins (DPRs), such as poly-GR, can be produced by this hexanucleotide expansion that disrupt a number of cellular processes, potentially contributing to neural degeneration. To better discern which of these mechanisms leads to disease-associated changes in patient brains, we analyzed gene expression data generated from the cortex and cerebellum. We found that transcripts encoding heat shock proteins (HSPs) regulated by the HSF1 transcription factor were significantly induced in C9ORF72-ALS/FTLD patients relative to both sporadic ALS/FTLD cases and controls. Treatment of human neurons with chemically synthesized DPRs was sufficient to activate a similar transcriptional response. Expression of GGGGCC repeats and also poly-GR in the brains of Drosophila lead to the upregulation of HSF1 and the same highly-conserved HSPs. Additionally, HSF1 was a modifier of poly-GR toxicity in Drosophila. Our results suggest that the expression of DPRs are associated with upregulation of HSF1 and activation of a heat shock response in C9ORF72-ALS/FTLD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-018-0555-8) contains supplementary material, which is available to authorized users. BioMed Central 2018-07-04 /pmc/articles/PMC6031111/ /pubmed/29973287 http://dx.doi.org/10.1186/s40478-018-0555-8 Text en © The Author(s). 2018 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 Mordes, Daniel A. Prudencio, Mercedes Goodman, Lindsey D. Klim, Joseph R. Moccia, Rob Limone, Francesco Pietilainen, Olli Chowdhary, Kaitavjeet Dickson, Dennis W. Rademakers, Rosa Bonini, Nancy M. Petrucelli, Leonard Eggan, Kevin Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients |
title | Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients |
title_full | Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients |
title_fullStr | Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients |
title_full_unstemmed | Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients |
title_short | Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients |
title_sort | dipeptide repeat proteins activate a heat shock response found in c9orf72-als/ftld patients |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031111/ https://www.ncbi.nlm.nih.gov/pubmed/29973287 http://dx.doi.org/10.1186/s40478-018-0555-8 |
work_keys_str_mv | AT mordesdaniela dipeptiderepeatproteinsactivateaheatshockresponsefoundinc9orf72alsftldpatients AT prudenciomercedes dipeptiderepeatproteinsactivateaheatshockresponsefoundinc9orf72alsftldpatients AT goodmanlindseyd dipeptiderepeatproteinsactivateaheatshockresponsefoundinc9orf72alsftldpatients AT klimjosephr dipeptiderepeatproteinsactivateaheatshockresponsefoundinc9orf72alsftldpatients AT mocciarob dipeptiderepeatproteinsactivateaheatshockresponsefoundinc9orf72alsftldpatients AT limonefrancesco dipeptiderepeatproteinsactivateaheatshockresponsefoundinc9orf72alsftldpatients AT pietilainenolli dipeptiderepeatproteinsactivateaheatshockresponsefoundinc9orf72alsftldpatients AT chowdharykaitavjeet dipeptiderepeatproteinsactivateaheatshockresponsefoundinc9orf72alsftldpatients AT dicksondennisw dipeptiderepeatproteinsactivateaheatshockresponsefoundinc9orf72alsftldpatients AT rademakersrosa dipeptiderepeatproteinsactivateaheatshockresponsefoundinc9orf72alsftldpatients AT bonininancym dipeptiderepeatproteinsactivateaheatshockresponsefoundinc9orf72alsftldpatients AT petrucellileonard dipeptiderepeatproteinsactivateaheatshockresponsefoundinc9orf72alsftldpatients AT eggankevin dipeptiderepeatproteinsactivateaheatshockresponsefoundinc9orf72alsftldpatients |