Characterization of HTT Inclusion Size, Location, and Timing in the zQ175 Mouse Model of Huntington´s Disease: An In Vivo High-Content Imaging Study

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. Major pathological hallmarks of HD include inclusions of mutant huntingtin (mHTT) protein, loss of neurons predominantly in the caudate nucleus, and at...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2015-04, Vol.10 (4), p.e0123527
Main Authors: Carty, Nikisha, Berson, Nadège, Tillack, Karsten, Thiede, Christina, Scholz, Diana, Kottig, Karsten, Sedaghat, Yalda, Gabrysiak, Christina, Yohrling, George, von der Kammer, Heinz, Ebneth, Andreas, Mack, Volker, Munoz-Sanjuan, Ignacio, Kwak, Seung
Format: Article
Language:English
Subjects:
Age
Atrophy
Automation
Brain
Caudate nucleus
Cortex
Hereditary diseases
Huntingtin
Huntington's disease
Huntingtons disease
In vivo methods and tests
Inclusion bodies
Inclusions
Laboratories
Mice
Neostriatum
Neurodegenerative diseases
Neuroimaging
Polyglutamine
Proteins
Quantitative analysis
Rodents
Studies
Transgenic animals
Trinucleotide repeats
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. Major pathological hallmarks of HD include inclusions of mutant huntingtin (mHTT) protein, loss of neurons predominantly in the caudate nucleus, and atrophy of multiple brain regions. However, the early sequence of histological events that manifest in region- and cell-specific manner has not been well characterized. Here we use a high-content histological approach to precisely monitor changes in HTT expression and characterize deposition dynamics of mHTT protein inclusion bodies in the recently characterized zQ175 knock-in mouse line. We carried out an automated multi-parameter quantitative analysis of individual cortical and striatal cells in tissue slices from mice aged 2–12 months and confirmed biochemical reports of an age-associated increase in mHTT inclusions in this model. We also found distinct regional and subregional dynamics for inclusion number, size and distribution with subcellular resolution. We used viral-mediated suppression of total HTT in the striatum of zQ175 mice as an example of a therapeutically-relevant but heterogeneously transducing strategy to demonstrate successful application of this platform to quantitatively assess target engagement and outcome on a cellular basis.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0123527