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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.

Original publication

DOI

10.15252/emmm.201607486

Type

Journal article

Journal

EMBO Mol Med

Publication Date

07/2017

Volume

9

Pages

859 - 868

Keywords

C9orf72 , amyotrophic lateral sclerosis, biomarker, cerebrospinal fluid, frontotemporal dementia, Amyotrophic Lateral Sclerosis, Biomarkers, C9orf72 Protein, Cerebrospinal Fluid, Cross-Sectional Studies, Dipeptides, Frontotemporal Dementia, Gene Expression, Humans, Immunoassay, Peptides, Repetitive Sequences, Amino Acid