A021 Early detection of exon 1 Huntingtin aggregation in zQ175 brains by molecular and histological approaches
Year: 2024
Type: conference-paper
Abstract: Background Huntington-lowering approaches are a major focus for therapeutic intervention for Huntington’s disease. In evaluating these treatments, it will be important to understand how the targeting strategy affects (1) levels of the HTT1a and full-length HTT transcripts, (2) the soluble HTTexon1 and the full-length HTT proteins that they encode and (3) the subcellular location of HTT aggregation, dependent on the stage of disease at which the intervention was administered. Aims Here, we mapped the earliest ages at which the appearance of HTT aggregation could be detected throughout the brain in heterozygous zQ175 mice. Methods Ten CNS regions were collected from zQ175 and wild-type mice at monthly intervals from 1 – 6 months of age and used for homogeneous time-resolved fluorescence (HTRF). Perfused brains were also collected and used for immunohistochemistry with the S830 antibody. Results Immunohistochemistry detected aggregated HTT in the form of a diffuse nuclear immunostain in neuronal nuclei in the striatum, hippocampus and cortex by 2 months of age. By 6 months, nuclear and cytoplasmic inclusions were widely distributed throughout the brain. By HTRF, aggregation could be detected in the striatum and cortex from one month of age. HTRF showed that soluble HTTexon1 levels decreased over the 6-month period, whilst levels of soluble full-length mutant HTT remained unchanged. Conclusions These data support the hypothesis, that the HTTexon1 protein initiates the aggregation process in knock-in mouse models and paves the way for a detailed analysis of HTT aggregation in response to HTT-lowering treatments.
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402374580