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 V Rademakers, Nancy M. Bonini, Leonard Petrucelli, Kevin Eggan

Research output: Contribution to journalArticle

4 Citations (Scopus)

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

Fingerprint

Frontotemporal Lobar Degeneration
Heat-Shock Response
Dipeptides
Amyotrophic Lateral Sclerosis
Heat-Shock Proteins
Drosophila
Proteins
Up-Regulation
Gene Expression
Brain
Cerebellum
Transcription Factors
RNA
Neurons

Keywords

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

ASJC Scopus subject areas

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

Cite this

Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients. / Mordes, Daniel A.; Prudencio, Mercedes; Goodman, Lindsey D.; Klim, Joseph R.; Moccia, Rob; Limone, Francesco; Pietilainen, Olli; Chowdhary, Kaitavjeet; Dickson, Dennis W; Rademakers, Rosa V; Bonini, Nancy M.; Petrucelli, Leonard; Eggan, Kevin.

In: Acta Neuropathologica Communications, Vol. 6, No. 1, 04.07.2018.

Research output: Contribution to journalArticle

Mordes, Daniel A. ; Prudencio, Mercedes ; Goodman, Lindsey D. ; Klim, Joseph R. ; Moccia, Rob ; Limone, Francesco ; Pietilainen, Olli ; Chowdhary, Kaitavjeet ; Dickson, Dennis W ; Rademakers, Rosa V ; Bonini, Nancy M. ; Petrucelli, Leonard ; Eggan, Kevin. / Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients. In: Acta Neuropathologica Communications. 2018 ; Vol. 6, No. 1.
@article{c31e8df73fd0464f9807e36908b15902,
title = "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 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.",
keywords = "Amyotrophic lateral sclerosis, C9ORF72 repeat expansion, Dipeptide repeat proteins, Drosophila, Frontotemporal dementia, Frontotemporal lobar degeneration, Heat shock response, HSF1",
author = "Mordes, {Daniel A.} and Mercedes Prudencio and Goodman, {Lindsey D.} and Klim, {Joseph R.} and Rob Moccia and Francesco Limone and Olli Pietilainen and Kaitavjeet Chowdhary and Dickson, {Dennis W} and Rademakers, {Rosa V} and Bonini, {Nancy M.} and Leonard Petrucelli and Kevin Eggan",
year = "2018",
month = "7",
day = "4",
doi = "10.1186/s40478-018-0555-8",
language = "English (US)",
volume = "6",
journal = "Acta neuropathologica communications",
issn = "2051-5960",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients

AU - Mordes, Daniel A.

AU - Prudencio, Mercedes

AU - Goodman, Lindsey D.

AU - Klim, Joseph R.

AU - Moccia, Rob

AU - Limone, Francesco

AU - Pietilainen, Olli

AU - Chowdhary, Kaitavjeet

AU - Dickson, Dennis W

AU - Rademakers, Rosa V

AU - Bonini, Nancy M.

AU - Petrucelli, Leonard

AU - Eggan, Kevin

PY - 2018/7/4

Y1 - 2018/7/4

N2 - 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.

AB - 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.

KW - Amyotrophic lateral sclerosis

KW - C9ORF72 repeat expansion

KW - Dipeptide repeat proteins

KW - Drosophila

KW - Frontotemporal dementia

KW - Frontotemporal lobar degeneration

KW - Heat shock response

KW - HSF1

UR - http://www.scopus.com/inward/record.url?scp=85061643878&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061643878&partnerID=8YFLogxK

U2 - 10.1186/s40478-018-0555-8

DO - 10.1186/s40478-018-0555-8

M3 - Article

C2 - 29973287

AN - SCOPUS:85061643878

VL - 6

JO - Acta neuropathologica communications

JF - Acta neuropathologica communications

SN - 2051-5960

IS - 1

ER -