Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients
| العنوان: | Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients |
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| المؤلفون: | Olli Pietilainen, Rosa Rademakers, Dennis W. Dickson, Nancy M. Bonini, Lindsey D. Goodman, Kaitavjeet Chowdhary, Leonard Petrucelli, Joseph R. Klim, Mercedes Prudencio, Daniel A. Mordes, Francesco Limone, Rob Moccia, Kevin Eggan |
| المصدر: | Acta Neuropathologica Communications, Vol 6, Iss 1, Pp 1-13 (2018) Acta Neuropathologica Communications Acta neuropathologica communications |
| بيانات النشر: | Springer Science and Business Media LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Dipeptide repeat proteins, Neural degeneration, Eye, lcsh:RC346-429, Cohort Studies, Heat Shock Transcription Factors, C9orf72, Gene expression, HSF1, Neurons, Heat shock response, DNA Repeat Expansion, Stem Cells, Brain, Dipeptides, Frontotemporal lobar degeneration, 3. Good health, Cell biology, Female, Drosophila, Frontotemporal dementia, Signal Transduction, Biology, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Heat shock protein, Glial Fibrillary Acidic Protein, medicine, Animals, Humans, Heat shock, lcsh:Neurology. Diseases of the nervous system, C9orf72 Protein, C9ORF72 repeat expansion, Research, fungi, Amyotrophic lateral sclerosis, medicine.disease, Disease Models, Animal, 030104 developmental biology, Gene Expression Regulation, Human medicine, Neurology (clinical), Trinucleotide repeat expansion, Heat-Shock Response |
| الوصف: | 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. |
| تدمد: | 2051-5960 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ca82577fa5b788d69c11e67737f76856Test https://doi.org/10.1186/s40478-018-0555-8Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ca82577fa5b788d69c11e67737f76856 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20515960 |
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