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Quantification of Huntington's Disease Related Markers in the R6/2 Mouse Model
Estibaliz Etxeberria-Rekalde1, Saioa Alzola-Aldamizetxebarria1, Stefanie Flunkert1
1QPS Austria GmbH, Grambach, Austria.
Insights
Huntington's disease (HD) mouse models show altered motor neuron markers (Ctip2) and early neuroinflammation (TSPO). These findings offer new preclinical evaluation tools for potential HD therapies.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Huntington's disease (HD) is a fatal neurodegenerative disorder caused by CAG triplet expansions in the huntingtin gene.
- Neurodegeneration in HD impacts the striatum, cortex, and hippocampus, leading to motor and cognitive deficits.
- The R6/2 mouse model exhibits HD neuropathology, but lacks analysis of recently identified patient biomarkers.
Purpose of the Study:
- To analyze novel biomarkers, Ctip2 and translocator protein (TSPO), in the R6/2 mouse model of HD.
- To establish translational readouts for preclinical evaluation of therapeutic compounds.
- To assess Ctip2 as a marker for motor system neurons and TSPO for early neuroinflammation.
Main Methods:
- In-depth analysis of R6/2 mice.
- Assessment of mutant huntingtin aggregates, ubiquitination, and brain atrophy.
- Evaluation of tyrosine hydroxylase, Ctip2, vesicular acetylcholine transporter, glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba1), and TSPO.
Main Results:
- Validated known pathologies including mutant huntingtin aggregates and brain atrophy.
- Observed decreased tyrosine hydroxylase and Ctip2 levels, indicating motor system disturbance.
- Detected increased astrocytosis and microglial activation, with TSPO showing higher sensitivity for early neuroinflammation than GFAP and Iba1.
Conclusions:
- Ctip2 and TSPO are sensitive and translational biomarkers in the R6/2 HD mouse model.
- These markers facilitate preclinical evaluation of new therapeutic compounds for Huntington's disease.
- TSPO demonstrates superior sensitivity for detecting early neuroinflammation compared to GFAP and Iba1.
Abstract:
Huntington's disease (HD) is caused by an expansion of CAG triplets in the huntingtin gene, leading to severe neuropathological changes that result in a devasting and lethal phenotype. Neurodegeneration in HD begins in the striatum and spreads to other brain regions such as cortex and hippocampus, causing motor and cognitive dysfunctions. To understand the signaling pathways involved in HD, animal models that mimic the human pathology are used. The R6/2 mouse as model of HD was already shown to present major neuropathological changes in the caudate putamen and other brain regions, but recently established biomarkers in HD patients were yet not analyzed in these mice. We therefore performed an in-depth analysis of R6/2 mice to establish new and highly translational readouts focusing on Ctip2 as biological marker for motor system-related neurons and translocator protein (TSPO) as a promising readout for early neuroinflammation. Our results validate already shown pathologies like mutant huntingtin aggregates, ubiquitination, and brain atrophy, but also provide evidence for decreased tyrosine hydroxylase and Ctip2 levels as indicators of a disturbed motor system, while vesicular acetyl choline transporter levels as marker for the cholinergic system barely change. Additionally, increased astrocytosis and activated microglia were observed by GFAP, Iba1 and TSPO labeling, illustrating, that TSPO is a more sensitive marker for early neuroinflammation compared to GFAP and Iba1. Our results thus demonstrate a high sensitivity and translational value of Ctip2 and TSPO as new marker for the preclinical evaluation of new compounds in the R6/2 mouse model of HD.
