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Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin.
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.
Affiliation
  • Tan Z; Institute for Memory Impairment and Neurological Disorders, University of California-Irvine, Irvine, CA, USA.
  • Dai W; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
  • van Erp TG; Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, CA, USA.
  • Overman J; Department of Neurobiology and Behavior, University of California-Irvine, Irvine, CA, USA.
  • Demuro A; Department of Neurobiology and Behavior, University of California-Irvine, Irvine, CA, USA.
  • Digman MA; Laboratory for Fluorescence Dynamics, Department of Biomedical Engineering, University of California-Irvine, Irvine, CA, USA.
  • Hatami A; Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
  • Albay R; Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
  • Sontag EM; Department of Neurobiology and Behavior, University of California-Irvine, Irvine, CA, USA.
  • Potkin KT; Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, CA, USA.
  • Ling S; Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, CA, USA.
  • Macciardi F; Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, CA, USA.
  • Bunney WE; Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, CA, USA.
  • Long JD; Department of Psychiatry, University of Iowa, Iowa City, IA, USA.
  • Paulsen JS; Department of Biostatistics, University of Iowa, Iowa City, IA, USA.
  • Ringman JM; Department of Psychiatry, University of Iowa, Iowa City, IA, USA.
  • Parker I; Department of Neurology and Psychology, University of Iowa, Iowa City, IA, USA.
  • Glabe C; Department of Neurology, Easton Center for Alzheimer's Disease Research, University of California-Los Angeles, Los Angeles, CA, USA.
  • Thompson LM; Department of Neurobiology and Behavior, University of California-Irvine, Irvine, CA, USA.
  • Chiu W; Institute for Memory Impairment and Neurological Disorders, University of California-Irvine, Irvine, CA, USA.
  • Potkin SG; Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
Mol Psychiatry ; 20(11): 1286-93, 2015 Nov.
Article in En | MEDLINE | ID: mdl-26100538
ABSTRACT
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Peptides / Huntington Disease / Protein Aggregation, Pathological / Mutation / Nerve Tissue Proteins Limits: Animals / Female / Humans / Male Language: En Journal: Mol Psychiatry Journal subject: BIOLOGIA MOLECULAR / PSIQUIATRIA Year: 2015 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Peptides / Huntington Disease / Protein Aggregation, Pathological / Mutation / Nerve Tissue Proteins Limits: Animals / Female / Humans / Male Language: En Journal: Mol Psychiatry Journal subject: BIOLOGIA MOLECULAR / PSIQUIATRIA Year: 2015 Type: Article Affiliation country: United States