title: Characterization of HTT inclusion size, location, and timing in the zQ175 mouse model of Huntington's disease: an in vivo high-content imaging study.
abstract: 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.
authors: Evotec AG, Manfred Eigen Campus, Hamburg, Germany.
authors: Nikisha
authors: N
authors: Carty
authors: Evotec AG, Manfred Eigen Campus, Hamburg, Germany.
authors: Nadège
authors: N
authors: Berson
authors: Evotec AG, Manfred Eigen Campus, Hamburg, Germany.
authors: Karsten
authors: K
authors: Tillack
authors: Evotec AG, Manfred Eigen Campus, Hamburg, Germany.
authors: Christina
authors: C
authors: Thiede
authors: Evotec AG, Manfred Eigen Campus, Hamburg, Germany.
authors: Diana
authors: D
authors: Scholz
authors: Evotec AG, Manfred Eigen Campus, Hamburg, Germany.
authors: Karsten
authors: K
authors: Kottig
authors: Evotec AG, Manfred Eigen Campus, Hamburg, Germany.
authors: Yalda
authors: Y
authors: Sedaghat
authors: Evotec AG, Manfred Eigen Campus, Hamburg, Germany.
authors: Christina
authors: C
authors: Gabrysiak
authors: CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America.
authors: George
authors: G
authors: Yohrling
authors: Evotec AG, Manfred Eigen Campus, Hamburg, Germany.
authors: Heinz
authors: H
authors: von der Kammer
authors: Evotec AG, Manfred Eigen Campus, Hamburg, Germany.
authors: Andreas
authors: A
authors: Ebneth
authors: Evotec AG, Manfred Eigen Campus, Hamburg, Germany.
authors: Volker
authors: V
authors: Mack
authors: CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America.
authors: Ignacio
authors: I
authors: Munoz-Sanjuan
authors: CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America.
authors: Seung
authors: S
authors: Kwak
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006579:Heterozygote; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002479:Inclusion Bodies; D045586:Intranuclear Inclusion Bodies; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D066263:Protein Aggregation, Pathological; D021381:Protein Transport
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins