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Acta Neuropathol Commun DOI:10.1186/s40478-018-0555-8

Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients.

Publication TypeJournal Article
Year of Publication2018
AuthorsMordes, DA, Prudencio, M, Goodman, LD, Klim, JR, Moccia, R, Limone, F, Pietilainen, O, Chowdhary, K, Dickson, DW, Rademakers, R, Bonini, NM, Petrucelli, L, Eggan, K
JournalActa Neuropathol Commun
Date Published2018 07 04
KeywordsAnimals, Brain, C9orf72 Protein, Cohort Studies, Dipeptides, Disease Models, Animal, DNA Repeat Expansion, Drosophila, Eye, Female, Frontotemporal Lobar Degeneration, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Heat Shock Transcription Factors, Heat-Shock Response, Humans, Male, Neurons, Signal Transduction, Stem Cells

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.


Alternate JournalActa Neuropathol Commun
PubMed ID29973287
PubMed Central IDPMC6031111
Grant ListR01 NS089742 / NS / NINDS NIH HHS / United States
R35 NS097273 / NS / NINDS NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
R01 NS063964 / NS / NINDS NIH HHS / United States
P50 AG005134 / AG / NIA NIH HHS / United States
T32 CA009216 / CA / NCI NIH HHS / United States
R01 NS088689 / NS / NINDS NIH HHS / United States
P01 NS084974 / NS / NINDS NIH HHS / United States
R21 NS084528 / NS / NINDS NIH HHS / United States
R01 ES020395 / ES / NIEHS NIH HHS / United States
R35 NS097275 / NS / NINDS NIH HHS / United States
R01 NS077402 / NS / NINDS NIH HHS / United States