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Mutated Huntingtin Causes Testicular Pathology in Transgenic Minipig Boars

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MACAKOVA Monika BOHUSLAVOVA Bozena VOCHOZKOVA Petra PAVLOK Antonin SEDLÁČKOVÁ Miroslava VIDINSKA Daniela VOCHYANOVA Klara LISKOVA Irena VALEKOVA Ivona BAXA Monika ELLEDEROVA Zdenka KLIMA Jiri JUHAS Stefan JUHASOVA Jana KLOUCKOVA Jana HALUZIK Martin KLEMPIR Jiri HANSIKOVA Hana SPACILOVA Jana COLLINS Ryan BLUMENTHAL Ian TALKOWSKI Michael GUSELLA James F. HOWLAND David S. DIFIGLIA Marian MOTLIK Jan

Rok publikování 2016
Druh Článek v odborném periodiku
Časopis / Zdroj Neurodegenerative Diseases
Fakulta / Pracoviště MU

Lékařská fakulta

Citace
Doi http://dx.doi.org/10.1159/000443665
Obor Neurologie, neurochirurgie, neurovědy
Klíčová slova Huntington’s disease; Pig model; Mutant huntingtin; Spermatozoa; Testes; Degeneration
Popis 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.

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