Year: 2024
Type: conference-abstract
Abstract: Background Huntington’s disease (HD) is a neurodegenerative disorder marked by neuron loss, neuroinflammation, oxidative stress, and disrupted metabolism. These changes are also detectable in body fluids, indicating peripheral homeostasis disruption. Aims This study aims to identify early molecular changes in pre-symptomatic knock-in minipigs (KI-85Q-HD) to find clinical markers for HD onset and progression. Methods Plasma and cerebrospinal fluid (CSF) were collected from minipigs aged 24, 30, 36, 42, and 48 months for biomarker analysis. We also isolated polymorphonuclear blood cells (PBMC) and fibroblasts for qPCR analysis of metabolic and antioxidant gene levels, and DNA damage. A Mito stress test was performed on fibroblasts from 42-month-old minipigs. Concurrently, motor and cognitive tests were conducted. Results Biomarker analysis showed increased soluble mutant huntingtin in CSF and plasma, peaking at 36 months, with a tendency toward increasing neurofilament light chain (NfL) in CSF with age. From 24 to 48 months, alkaline phosphatase (ALP) activity in plasma increased. Cytokine measurements indicated elevated IL-1RA in CSF and higher IL-12 levels up to 42 months, while plasma IL-1RA decreased. qPCR analysis revealed increased mitochondrial complex I subunit (ND1) expression in fibroblasts and reduced coupling efficiency at 42 months. Sex-based analysis showed increased PGC1a, a mitochondrial regulator, and NEIL2, a DNA glycosylase, in male fibroblasts, along with decreased maximal and spare respiratory capacity. Behavioral tests indicated motor deficits, particularly in Balance beam and Treadmill test performance. Conclusions The KI-85Q-HD minipig model exhibits biochemical changes in CSF and periphery before significant HD symptoms. Fibroblast results suggest possible sex-dependent HD onset. Support CHDI Foundation, Czech Academy of Sciences - Strategy AV21 (VP29), Johannes Amos Comenius Programme (Research Excellence in Regenerative medicine, CZ.02.01.01/00/22_008/0004562).
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402373967