Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients
Abstract 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 pathogenes...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-07-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-018-0555-8 |
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| author | Daniel A. Mordes Mercedes Prudencio Lindsey D. Goodman Joseph R. Klim Rob Moccia Francesco Limone Olli Pietilainen Kaitavjeet Chowdhary Dennis W. Dickson Rosa Rademakers Nancy M. Bonini Leonard Petrucelli Kevin Eggan |
| author_facet | Daniel A. Mordes Mercedes Prudencio Lindsey D. Goodman Joseph R. Klim Rob Moccia Francesco Limone Olli Pietilainen Kaitavjeet Chowdhary Dennis W. Dickson Rosa Rademakers Nancy M. Bonini Leonard Petrucelli Kevin Eggan |
| author_sort | Daniel A. Mordes |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-10T18:27:40Z |
| format | Article |
| id | doaj.art-7dff6ba8c98d431088d6dde5e87fa681 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-10T18:27:40Z |
| publishDate | 2018-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-7dff6ba8c98d431088d6dde5e87fa6812022-12-22T01:38:01ZengBMCActa Neuropathologica Communications2051-59602018-07-016111310.1186/s40478-018-0555-8Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patientsDaniel A. Mordes0Mercedes Prudencio1Lindsey D. Goodman2Joseph R. Klim3Rob Moccia4Francesco Limone5Olli Pietilainen6Kaitavjeet Chowdhary7Dennis W. Dickson8Rosa Rademakers9Nancy M. Bonini10Leonard Petrucelli11Kevin Eggan12Department of Stem Cell and Regenerative Biology, Harvard UniversityDepartment of NeuroscienceDepartment of Biology, University of PennsylvaniaDepartment of Stem Cell and Regenerative Biology, Harvard UniversityDepartment of Stem Cell and Regenerative Biology, Harvard UniversityDepartment of Stem Cell and Regenerative Biology, Harvard UniversityDepartment of Stem Cell and Regenerative Biology, Harvard UniversityDepartment of Stem Cell and Regenerative Biology, Harvard UniversityDepartment of NeuroscienceDepartment of NeuroscienceDepartment of Biology, University of PennsylvaniaDepartment of NeuroscienceDepartment of Stem Cell and Regenerative Biology, Harvard UniversityAbstract 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.http://link.springer.com/article/10.1186/s40478-018-0555-8Amyotrophic lateral sclerosisC9ORF72 repeat expansionDipeptide repeat proteinsDrosophilaFrontotemporal dementiaFrontotemporal lobar degeneration |
| spellingShingle | Daniel A. Mordes Mercedes Prudencio Lindsey D. Goodman Joseph R. Klim Rob Moccia Francesco Limone Olli Pietilainen Kaitavjeet Chowdhary Dennis W. Dickson Rosa Rademakers Nancy M. Bonini Leonard Petrucelli Kevin Eggan Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients Acta Neuropathologica Communications Amyotrophic lateral sclerosis C9ORF72 repeat expansion Dipeptide repeat proteins Drosophila Frontotemporal dementia Frontotemporal lobar degeneration |
| 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 | Amyotrophic lateral sclerosis C9ORF72 repeat expansion Dipeptide repeat proteins Drosophila Frontotemporal dementia Frontotemporal lobar degeneration |
| url | http://link.springer.com/article/10.1186/s40478-018-0555-8 |
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