Poly-GP in cerebrospinal fluid links C9orf72-associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD

EMBO Mol Med. 2017 Jul;9(7):859-868. doi: 10.15252/emmm.201607486.

Abstract

The C9orf72 GGGGCC repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). Non-conventional repeat translation results in five dipeptide repeat proteins (DPRs), but their clinical utility, overall significance, and temporal course in the pathogenesis of c9ALS/FTD are unclear, although animal models support a gain-of-function mechanism. Here, we established a poly-GP immunoassay from cerebrospinal fluid (CSF) to identify and characterize C9orf72 patients. Significant poly-GP levels were already detectable in asymptomatic C9orf72 mutation carriers compared to healthy controls and patients with other neurodegenerative diseases. The poly-GP levels in asymptomatic carriers were similar to symptomatic c9ALS/FTD cases. Poly-GP levels were not correlated with disease onset, clinical scores, and CSF levels of neurofilaments as a marker for axonal damage. Poly-GP determination in CSF revealed a C9orf72 mutation carrier in our cohort and may thus be used as a diagnostic marker in addition to genetic testing to screen patients. Presymptomatic expression of poly-GP and likely other DPR species may contribute to disease onset and thus represents an alluring therapeutic target.

Keywords: C9orf72; amyotrophic lateral sclerosis; biomarker; cerebrospinal fluid; frontotemporal dementia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / diagnosis*
  • Amyotrophic Lateral Sclerosis / pathology
  • Biomarkers / cerebrospinal fluid*
  • C9orf72 Protein / genetics*
  • Cerebrospinal Fluid / chemistry
  • Cross-Sectional Studies
  • Dipeptides / genetics*
  • Frontotemporal Dementia / diagnosis*
  • Frontotemporal Dementia / pathology
  • Gene Expression
  • Humans
  • Immunoassay
  • Peptides / cerebrospinal fluid*
  • Repetitive Sequences, Amino Acid

Substances

  • Biomarkers
  • C9orf72 Protein
  • C9orf72 protein, human
  • Dipeptides
  • Peptides