Poly-GP in cerebrospinal fluid links C9orf72-associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD.
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.
['Lehmer|Carina|C|', 'Oeckl|Patrick|P|', 'Weishaupt|Jochen H|JH|', 'Volk|Alexander E|AE|', 'Diehl-Schmid|Janine|J|', 'Schroeter|Matthias L|ML|', 'Lauer|Martin|M|', 'Kornhuber|Johannes|J|', 'Levin|Johannes|J|', 'Fassbender|Klaus|K|', 'Landwehrmeyer|Bernhard|B|', '|||', 'Schludi|Martin H|MH|', 'Arzberger|Thomas|T|', 'Kremmer|Elisabeth|E|', 'Flatley|Andrew|A|', 'Feederle|Regina|R|', 'Steinacker|Petra|P|', 'Weydt|Patrick|P|', 'Ludolph|Albert C|AC|', 'Edbauer|Dieter|D|0000-0002-7186-4653', 'Otto|Markus|M|0000-0003-4273-4267']
D000690:Amyotrophic Lateral Sclerosis D015415:Biomarkers D000073885:C9orf72 Protein D002555:Cerebrospinal Fluid D003430:Cross-Sectional Studies D004151:Dipeptides D057180:Frontotemporal Dementia D015870:Gene Expression D006801:Humans D007118:Immunoassay D010455:Peptides D020449:Repetitive Sequences, Amino Acid
cerebrospinal fluid C9orf72 amyotrophic lateral sclerosis frontotemporal dementia biomarker