Journal Article

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

Rademakers, Rosa, Dickson, Dennis W., Eggan, Kevin, Moccia, Rob, Pietilainen, Olli, Prudencio, Mercedes, Petrucelli, Leonard, Limone, Francesco, Chowdhary, Kaitavjeet, Klim, Joseph R., Bonini, Nancy M., Mordes, Daniel A., Goodman, Lindsey D.

2018

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Nature Publishing Group,BMC
• Subject: Amyotrophic lateral sclerosis / Animals / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Brain / Brain - metabolism / Brain - pathology / C9orf72 Protein - genetics / C9ORF72 repeat expansion / Cohort Studies / Dipeptide repeat proteins / Dipeptides / Disease / Disease Models, Animal / DNA Repeat Expansion - genetics / Drosophila / Eye - pathology / Female / Frontotemporal dementia / Frontotemporal lobar degeneration / Frontotemporal Lobar Degeneration - genetics / Frontotemporal Lobar Degeneration - pathology / Gene expression / Gene Expression Regulation - genetics / Generalized linear models / Genes / Genetic aspects / Glial Fibrillary Acidic Protein - metabolism / Heat shock proteins / Heat Shock Transcription Factors - genetics / Heat Shock Transcription Factors - metabolism / Heat-Shock Response - physiology / Humans / Male / Neurology / Neurons / Neurons - metabolism / Neurosciences / Ontology / Pathology / Patients / Proteins / Signal Transduction - physiology / Stem cells / Stem Cells - metabolism / Values