Mitochondrial Metabolism in a Large-Animal Model of Huntington Disease: The Hunt for Biomarkers in the Spermatozoa of Presymptomatic Minipigs
Language English Country Switzerland Media print-electronic
Document type Journal Article
PubMed
28633139
DOI
10.1159/000475467
PII: 000475467
Knihovny.cz E-resources
- Keywords
- Huntington disease, Large-animal model, Mitochondrial metabolism, Mutant huntingtin, Spermatozoa,
- MeSH
- Respiration MeSH
- Animals, Genetically Modified MeSH
- Huntington Disease complications genetics pathology MeSH
- Tricarboxylic Acids metabolism MeSH
- Humans MeSH
- Swine, Miniature MeSH
- Mitochondrial Proteins metabolism MeSH
- Mitochondria metabolism MeSH
- Mutation genetics MeSH
- Oxidative Phosphorylation MeSH
- Swine MeSH
- Huntingtin Protein genetics MeSH
- Pyruvate Dehydrogenase Complex metabolism MeSH
- Semen metabolism MeSH
- Spermatozoa metabolism pathology MeSH
- Trinucleotide Repeats genetics MeSH
- Age Factors MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- HTT protein, human MeSH Browser
- Tricarboxylic Acids MeSH
- Mitochondrial Proteins MeSH
- Huntingtin Protein MeSH
- Pyruvate Dehydrogenase Complex MeSH
BACKGROUND: Huntington disease (HD) is a fatal neurodegenerative disorder involving reduced muscle coordination, mental and behavioral changes, and testicular degeneration. In order to further clarify the decreased fertility and penetration ability of the spermatozoa of transgenic HD minipig boars (TgHD), we applied a set of mitochondrial metabolism (MM) parameter measurements to this promising biological material, which can be collected noninvasively in longitudinal studies. OBJECTIVE: We aimed to optimize methods for MM measurements in spermatozoa and to establish possible biomarkers of HD in TgHD spermatozoa expressing the N-terminal part of mutated human huntingtin. METHODS: Semen samples from 12 TgHD and wild-type animals, aged 12-65 months, were obtained repeatedly during the study. Respiration was measured by polarography, MM was assessed by the detection of oxidation of radiolabeled substrates (mitochondrial energy-generating system; MEGS), and the content of the oxidative phosphorylation system subunits was detected by Western blot. Three possibly interfering factors were statistically analyzed: the effect of HD, generation and aging. RESULTS: We found 5 MM parameters which were significantly diminished in TgHD spermatozoa and propose 3 specific MEGS incubations and complex I-dependent respiration as potential biomarkers of HD in TgHD spermatozoa. CONCLUSIONS: Our results suggest a link between the gain of toxic function of mutated huntingtin in TgHD spermatozoa and the observed MM and/or glycolytic impairment. We determined 4 biomarkers useful for HD phenotyping and experimental therapy monitoring studies in TgHD minipigs.
References provided by Crossref.org
Large Animal Models of Huntington's Disease: What We Have Learned and Where We Need to Go Next
Transgenic minipig model of Huntington's disease exhibiting gradually progressing neurodegeneration
