Huntington’s disease cerebrospinal fluid seeds aggregation of mutant huntingtin

• Published in: Molecular psychiatry Vol. 20; no. 11; pp. 1286 - 1293
• Main Authors: Tan, Z, Dai, W, van Erp, T G M, Overman, J, Demuro, A, Digman, M A, Hatami, A, Albay, R, Sontag, E M, Potkin, K T, Ling, S, Macciardi, F, Bunney, W E, Long, J D, Paulsen, J S, Ringman, J M, Parker, I, Glabe, C, Thompson, L M, Chiu, W, Potkin, S G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2015; Nature Publishing Group
• Subjects: 13/109; 13/44; 14/35; 14/69; 692/53/2423; 692/699; 82/51; 82/80; Aggregates; Alzheimer's disease; Animals; Behavioral Sciences; Biochemistry; Biological Psychology; Biomarkers; Cells, Cultured; Cerebrospinal fluid; Dementia; Female; Gene mutations; Genetic aspects; Health aspects; Humans; Huntingtin Protein; Huntington Disease - cerebrospinal fluid; Huntington Disease - genetics; Huntington's chorea; Huntingtons disease; Immediate Communication; Male; Medical research; Medicine; Medicine & Public Health; Microscopy; Microscopy, Electron; Molecular biology; Mutation; Nerve Tissue Proteins - genetics; Neurological disorders; Neurology; Neurosciences; Peptides; Peptides - cerebrospinal fluid; Pharmacotherapy; Physiological aspects; Propagation; Protein Aggregation, Pathological - cerebrospinal fluid; Protein Aggregation, Pathological - pathology; Proteins; Psychiatry; Rats; Rats, Transgenic; Risk factors; Seeds; Transfection; United States; Los Angeles California; Iowa City Iowa; California; United States > US
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/mp.2015.81

Huntington’s disease (HD), a progressive neurodegenerative disease, is caused by an expanded CAG triplet repeat producing a mutant huntingtin protein (mHTT) with a polyglutamine-repeat expansion. Onset of symptoms in mutant huntingtin gene-carrying individuals remains unpredictable. We report that synthetic polyglutamine oligomers and cerebrospinal fluid (CSF) from BACHD transgenic rats and from human HD subjects can seed mutant huntingtin aggregation in a cell model and its cell lysate. Our studies demonstrate that seeding requires the mutant huntingtin template and may reflect an underlying prion-like protein propagation mechanism. Light and cryo-electron microscopy show that synthetic seeds nucleate and enhance mutant huntingtin aggregation. This seeding assay distinguishes HD subjects from healthy and non-HD dementia controls without overlap (blinded samples). Ultimately, this seeding property in HD patient CSF may form the basis of a molecular biomarker assay to monitor HD and evaluate therapies that target mHTT.