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

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

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Number of pages1
JournalActa Neuropathologica Communications
Volume6
Issue number1
DOIs
StatePublished - Jul 4 2018

Keywords

  • Amyotrophic lateral sclerosis
  • C9ORF72 repeat expansion
  • Dipeptide repeat proteins
  • Drosophila
  • Frontotemporal dementia
  • Frontotemporal lobar degeneration
  • HSF1
  • Heat shock response

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients'. Together they form a unique fingerprint.

  • Cite this