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14 HD Insights, Vol. 12 Copyright © Huntington Study Group 2015. All rights reserved. H D I N S I G H T S Research Round-Up: Insights, cont... Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin By: Tan Z, Dai W, van Erp TG, Overman J, Demuro A, Digman MA, Hatami A, Albay R, Sontag EM, Potkin KT, Ling S, Macciardi F, Bunney WE, Long JD, Paulsen JS, Ringman JM, Parker I, Glabe C, Thompson LM, Chiu W, Potkin SG (Summary by Zhiqun Tan, PhD, and Steven G. Potkin, MD) The onset of symptoms in individuals who carry the mutant HD allele (mHTT) remains variable and unpredictable. To speed development of new therapies, biomarkers that reflect the development of the HD pathological process are quantitatively associated with the course of illness are needed. We reported that oligomeric peptides that contain the polyglutamine expansion coded by mHTT, and CSF fluid from individuals with HD, and BACHD transgenic rats, enhance seeded aggregation in a PC-12 cell model and its cell lysate. Oligomers derived from other proteins, including Aβ and α-synuclein, do not induce seeding. We demonstrate that seeding is mHTT template-specific and may reflect an underlying cell-to-cell mechanism of huntingtinopathy propagation. Light and cryo-electron microscopy (cryo-EM) confirm that synthetic seeds nucleate and enhance mHTT aggregation in cell lysates. This seeding assay (Figure) distinguishes individuals with HD from healthy controls. Seeding measures in asymptomatic gene-positive individuals fall between HD patients and controls. This quantifiable seeding property in the CSF of individuals with HD may serve as a molecular biomarker assay to monitor HD progression, and to evaluate therapies that target mHTT. The automation of the assay is in process. Figure: Schematic of mutant Huntingtin (mHTT) aggregation assays using whole-cell lysates (supernatants, middle of figure) and enhanced aggregation in whole cells prepared from the PC-12 cell model of HD H D I N S I G H T S T M T H A N K S R A P T O R F O R I T S G E N E R O U S S U P P O R T Tan Z, Dai W, van Erp TG, et al. Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin. Mol Psychiatry. 2015 Jun 23. doi: 10.1038/mp.2015.81. [Epub ahead of print]