Abstract
ABSTRACTHuntington's disease (HD) is a monogenic, progressive, neurodegenerative disorder with currently no available treatment. The Libechov transgenic minipig model for HD (TgHD) displays neuroanatomical similarities to humans and exhibits slow disease progression, and is therefore more powerful than available mouse models for the development of therapy. The phenotypic characterization of this model is still ongoing, and it is essential to validate biomarkers to monitor disease progression and intervention. In this study, the behavioral phenotype (cognitive, motor and behavior) of the TgHD model was assessed, along with biomarkers for mitochondrial capacity, oxidative stress, DNA integrity and DNA repair at different ages (24, 36 and 48 months), and compared with age-matched controls. The TgHD minipigs showed progressive accumulation of the mutant huntingtin (mHTT) fragment in brain tissue and exhibited locomotor functional decline at 48 months. Interestingly, this neuropathology progressed without any significant age-dependent changes in any of the other biomarkers assessed. Rather, we observed genotype-specific effects on mitochondrial DNA (mtDNA) damage, mtDNA copy number, 8-oxoguanine DNA glycosylase activity and global level of the epigenetic marker 5-methylcytosine that we believe is indicative of a metabolic alteration that manifests in progressive neuropathology. Peripheral blood mononuclear cells (PBMCs) were relatively spared in the TgHD minipig, probably due to the lack of detectable mHTT. Our data demonstrate that neuropathology in the TgHD model has an age of onset of 48 months, and that oxidative damage and electron transport chain impairment represent later states of the disease that are not optimal for assessing interventions.This article has an associated First Person interview with the first author of the paper.
Highlights
Huntington’s disease (HD) is a devastating neurodegenerative disease for which there are currently no disease-modifying treatments
The pooled samples revealed a reduced level of mitochondrial DNA damage in the basal ganglia in transgenic minipig model for HD (TgHD) minipigs, whereas the corresponding levels in the frontal cortex and in Peripheral blood mononuclear cells (PBMCs) were normal (Fig. 2A, P=0.01)
Nuclear DNA damage was not significantly altered in any of the tested tissues in TgHD minipigs (Fig. 2B), thereby contrasting the situation seen in human PBMCs
Summary
Huntington’s disease (HD) is a devastating neurodegenerative disease for which there are currently no disease-modifying treatments. HD is inherited in an autosomal-dominant manner and caused by a trinucleotide CAG expansion in exon 1 of the huntingtin gene (HTT), resulting in the expression of mutant huntingtin (mHTT). It is clinically characterized by cognitive, psychiatric and motor dysfunctions, along with weight loss and muscle wasting. These symptoms stem from the characteristic striatal neurodegeneration, thought to be the neuropathological hallmark of the disease. The CAG repeat size negatively correlates with the age of onset of the disease and explains most of the variation in age at motor onset, with the remaining variance being currently unidentified genetic and environmental factors. The fragments can be produced by proteolytic cleavage of the full-length mHTT or alternative splicing (Miller et al, 2010; Sathasivam et al, 2013)
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