Testicular degeneration in Huntington disease

Raamsdonk, Jeremy M. Van; Murphy, Zoe; Selva, David M.; Hamidizadeh, Ramin; Pearson, Jacqueline; Petersén, Åsa; Björkqvist, Maria; Muir, Carlyn; Mackenzie, Ian R.; Hammond, Geoffrey L.; Vogl, A. Wayne; Hayden, Michael R.; Leavitt, Blair R.

doi:10.1016/j.nbd.2007.01.006

Cited by 88 publications

(78 citation statements)

References 51 publications

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“…Interestingly, among all organs, the testes display the most comparable gene expression pattern to the brain [10]. In accordance with this finding, the expression of mtHtt in R6/2 and YAC128 mouse models of HD results in atrophy of the brain and testes [11,12,13]. Closer examination of the testes in YAC128 mice revealed disorganized seminiferous epithelium and a reduced number of germ cells.…”

Section: Introductionmentioning

confidence: 71%

“…YAC72 mice expressing mtHtt but lacking endogenous Htt (YAC72 -/- ) revealed an even more severe phenotype resulting in infertility with aspermia and massive apoptotic cell death in the testes [14]. Also, a detailed testes examination in HD patients documented testicular abnormalities as well as reduced numbers of germ cells and abnormal morphology of seminiferous tubules [13]. …”

Section: Introductionmentioning

confidence: 99%

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Mutated Huntingtin Causes Testicular Pathology in Transgenic Minipig Boars

Macakova

Bohuslavová²,

Vochozková³

et al. 2016

Neurodegener Dis

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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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Section: Introductionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Mutated Huntingtin Causes Testicular Pathology in Transgenic Minipig Boars

Macakova

Bohuslavová²,

Vochozková³

et al. 2016

Neurodegener Dis

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“…These results indicate that Htt has a crucial function in spermatogenesis. It is known that Huntington's disease patients and animal models have specific testicular pathology with reduced numbers of germ cells and abnormal seminiferous tubule morphology (Van Raamsdonk et al, 2007). We speculate that the testicular degeneration in Huntington's disease patients and mouse models might be attributable to the partial loss of normal Htt function.…”

Section: Discussionmentioning

confidence: 86%

“…Htt is a large protein with unknown function that is expressed ubiquitously at low levels during early development and at high levels in the testis and in neurons of the brain (Van Raamsdonk et al, 2007). Within the cell, mammalian Htt is associated with a variety of organelles, including the nucleus, endoplasmic reticulum, Golgi complex and mitochondrion.…”

Section: Introductionmentioning

confidence: 99%

Germline deletion of huntingtin causes male infertility and arrested spermiogenesis in mice

Yan

Zhang

Liu

et al. 2016

Journal of Cell Science

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Human Huntingtin (HTT), a Huntington's disease gene, is highly expressed in the mammalian brain and testis. Simultaneous knockout of mouse Huntingtin (Htt) in brain and testis impairs male fertility, providing evidence for a link between Htt and spermatogenesis; however, the underlying mechanism remains unclear. To understand better the function of Htt in spermatogenesis, we restricted the genetic deletion specifically to the germ cells using the Cre/loxP sitespecific recombination strategy and found that the resulting mice manifested smaller testes, azoospermia and complete male infertility. Meiotic chromosome spread experiments showed that the process of meiosis was normal in the absence of Htt. Notably, we found that Httdeficient round spermatids did not progress beyond step 3 during the post-meiotic phase, when round spermatids differentiate into mature spermatozoa. Using an iTRAQ-based quantitative proteomic assay, we found that knockout of Htt significantly altered the testis protein profile. The differentially expressed proteins exhibited a remarkable enrichment for proteins involved in translation regulation and DNA packaging, suggesting that Htt might play a role in spermatogenesis by regulating translation and DNA packaging in the testis.

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“…Also, this neural and testicular expression of mtHtt also predominates in transgenic minipigs [20]. Intriguingly, reproductive disturbances were described both in human HD patients [21] as well as in transgenic (Tg) HD animal models, including our TgHD minipigs [20,21,22,23]. A decline in fertility in F1 generation TgHD boars caused by a reduced sperm count and penetration rate was first noticed at the age of 13 months and it remained constant until 26 months [24].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Metabolism in a Large-Animal Model of Huntington Disease: The Hunt for Biomarkers in the Spermatozoa of Presymptomatic Minipigs

Křížová

Stufkova²,

Rodinová³

et al. 2017

Neurodegener Dis

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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.

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Testicular degeneration in Huntington disease

Cited by 88 publications

References 51 publications

Mutated Huntingtin Causes Testicular Pathology in Transgenic Minipig Boars

Mutated Huntingtin Causes Testicular Pathology in Transgenic Minipig Boars

Germline deletion of huntingtin causes male infertility and arrested spermiogenesis in mice

Mitochondrial Metabolism in a Large-Animal Model of Huntington Disease: The Hunt for Biomarkers in the Spermatozoa of Presymptomatic Minipigs

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