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

EMBO Mol. Med. 9, 859-868 (2017)
Publishers Version Research data DOI PMC
Open Access Gold
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as soon as is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords C9orf72 ; Amyotrophic Lateral Sclerosis ; Biomarker ; Cerebrospinal Fluid ; Frontotemporal Dementia; C9orf72 Hexanucleotide Repeat; Frontotemporal Dementia; Ggggcc-repeat; Clinicopathological Correlations; Antisense Transcripts; Rna Foci; Proteins; Expansions; Als; C9ftd/als
Reviewing status
Institute(s) Monoclonal Antibody (MAB)
Institute of Diabetes and Obesity (IDO)