Mutated Huntingtin Causes Testicular Pathology in Transgenic Minipig Boars
Language English Country Switzerland Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
26959244
DOI
10.1159/000443665
PII: 000443665
Knihovny.cz E-resources
- MeSH
- Genetic Vectors MeSH
- Animals, Genetically Modified MeSH
- Huntington Disease metabolism pathology MeSH
- Lentivirus genetics MeSH
- Humans MeSH
- Swine, Miniature MeSH
- Disease Models, Animal MeSH
- Mutation * MeSH
- Sperm Count MeSH
- Swine MeSH
- Cell Proliferation physiology MeSH
- Huntingtin Protein genetics metabolism MeSH
- Spermatozoa metabolism pathology MeSH
- Aging metabolism pathology MeSH
- Testis metabolism pathology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- HTT protein, human MeSH Browser
- Huntingtin Protein MeSH
BACKGROUND: Huntington's disease is induced by CAG expansion in a single gene coding the huntingtin protein. The mutated huntingtin (mtHtt) primarily causes degeneration of neurons in the brain, but it also affects peripheral tissues, including testes. OBJECTIVE: We studied sperm and testes of transgenic boars expressing the N-terminal region of human mtHtt. METHODS: In this study, measures of reproductive parameters and electron microscopy (EM) images of spermatozoa and testes of transgenic (TgHD) and wild-type (WT) boars of F1 (24-48 months old) and F2 (12-36 months old) generations were compared. In addition, immunofluorescence, immunohistochemistry, Western blot, hormonal analysis and whole-genome sequencing were done in order to elucidate the effects of mtHtt. RESULTS: Evidence for fertility failure of both TgHD generations was observed at the age of 13 months. Reproductive parameters declined and progressively worsened with age. EM revealed numerous pathological features in sperm tails and in testicular epithelium from 24- and 36-month-old TgHD boars. Moreover, immunohistochemistry confirmed significantly lower proliferation activity of spermatogonia in transgenic testes. mtHtt was highly expressed in spermatozoa and testes of TgHD boars and localized in all cells of seminiferous tubules. Levels of fertility-related hormones did not differ in TgHD and WT siblings. Genome analysis confirmed that insertion of the lentiviral construct did not interrupt any coding sequence in the pig genome. CONCLUSIONS: The sperm and testicular degeneration of TgHD boars is caused by gain-of-function of the highly expressed mtHtt.
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
