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Lehmer, Carina; Öckl, Patrick; Weishaupt, Jochen H.; Volk, Alexander E.; Diehl-Schmid, Janine; Schröter, Matthias L.; Lauer, Martin; Kornhuber, Johannes; Levin, Johannes; Fassbender, Klaus; Landwehrmeyer, Bernhard; Schludi, Martin H.; Arzberger, Thomas; Kremmer, Elisabeth; Flatley, Andrew; Feederle, Regina; Steinacker, Petra; Weydt, Patrick; Ludolph, Albert C.; Edbauer, Dieter; Otto, Markus (2017): Poly-GP in cerebrospinal fluid links C9orf72-associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD. In: Embo Molecular Medicine, Vol. 9, No. 7: pp. 859-868
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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.