In the last two decades, a school of thought emerged that perceives male reproductive health, testicular function, and sperm output as a sentry for general, somatic health. Large-scale epidemiologic studies have already linked the reduced sperm count to increased risk of chronic somatic disease (e.g., cancer, cardiovascular, neurological and bone diseases), yet most of these studies have not taken full advantage of advanced andrological analysis. Altered proteostasis, i.e., the disbalance between protein synthesis and turnover, is a common denominator of many diseases, including but not limited to cancer and neurodegenerative diseases. This chapter introduces the concept of cellular proteostasis as a measure of sperm structural and functional integrity and an endpoint of varied impacts on spermiogenesis and sperm maturation, including heritability, general health, lifestyle, and occupational and environmental reprotoxic exposure. Special consideration is given to small molecule protein modifiers, sperm-binding seminal plasma proteins, zinc-interacting proteins, and redox proteins responsible for the maintenance of protein structure and the protection of spermatozoa from oxidative damage. While the main focus is on human male infertility, serious consideration is given to relevant animal models, and in particular to male food animals with extensive records of fertility from artificial insemination services. Altogether, the proteostatic biomarker discovery and validation studies set the stage for the integration of proteomics of sperm proteostasis with genomic and high throughput phenomic approaches to benefit both human and animal reproductive medicine.

• Klíčová slova
• Biomarker, Infertility, Omics, Proteasome, Proteostasis, Seminal plasma, Sperm, Thioredoxin, Ubiquitin,
• MeSH
• fertilita * fyziologie   MeSH
• homeostáze proteinů * fyziologie   MeSH
• lidé MeSH
• mužská infertilita * metabolismus   genetika   patologie   patofyziologie   MeSH
• spermatogeneze * MeSH
• spermie * metabolismus   patologie   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Genetically modified rodent models of Huntington's disease (HD) have been especially valuable to our understanding of HD pathology and the mechanisms by which the mutant HTT gene alters physiology. However, due to inherent differences in genetics, neuroanatomy, neurocircuitry and neurophysiology, animal models do not always faithfully or fully recapitulate human disease features or adequately predict a clinical response to treatment. Therefore, conducting translational studies of candidate HD therapeutics only in a single species (i.e. mouse disease models) may not be sufficient. Large animal models of HD have been shown to be valuable to the HD research community and the expectation is that the need for translational studies that span rodent and large animal models will grow. Here, we review the large animal models of HD that have been created to date, with specific commentary on differences between the models, the strengths and disadvantages of each, and how we can advance useful models to study disease pathophysiology, biomarker development and evaluation of promising therapeutics.

• Klíčová slova
• Minipigs, nonhuman primates, sheep, therapeutics,
• MeSH
• geneticky modifikovaná zvířata * MeSH
• Huntingtonova nemoc * genetika   patologie   patofyziologie   terapie   MeSH
• miniaturní prasata MeSH
• modely nemocí na zvířatech * MeSH
• ovce MeSH
• prasata MeSH
• primáti MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Huntington's disease (HD) is an inherited devastating neurodegenerative disease with no known cure to date. Several therapeutic treatments for HD are in development, but their safety, tolerability and efficacy need to be tested before translation to bedside. The monogenetic nature of this disorder has enabled the generation of transgenic animal models carrying a mutant huntingtin (mHTT) gene causing HD. A large animal model reflecting disease progression in humans would be beneficial for testing the potential therapeutic approaches. Progression of the motor, cognitive and behavioral phenotype was monitored in transgenic Huntington's disease minipigs (TgHD) expressing the N-terminal part of human mHTT. New tests were established to investigate physical activity by telemetry, and to explore the stress-induced behavioral and cognitive changes in minipigs. The longitudinal study revealed significant differences between 6- to 8-year-old TgHD animals and their wild-type (WT) controls in a majority of the tests. The telemetric study showed increased physical activity of 4.6- to 6.5-year-old TgHD boars compared to their WT counterparts during the lunch period as well as in the afternoon. Our phenotypic study indicates progression in adult TgHD minipigs and therefore this model could be suitable for longstanding preclinical studies of HD.This article has an associated First Person interview with the first author of the paper.

• Klíčová slova
• Cognitive and behavioral studies, Huntington's disease, Large animal model, Motor, Phenotyping,
• MeSH
• chování zvířat fyziologie   MeSH
• geneticky modifikovaná zvířata MeSH
• Huntingtonova nemoc komplikace   patofyziologie   MeSH
• jazyk MeSH
• kognice fyziologie   MeSH
• kondiční příprava zvířat MeSH
• longitudinální studie MeSH
• miniaturní prasata MeSH
• modely nemocí na zvířatech MeSH
• pohybová aktivita * MeSH
• prasata MeSH
• psychický stres komplikace   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Recently developed therapeutic approaches for the treatment of Huntington's disease (HD) require preclinical testing in large animal models. The minipig is a suitable experimental animal because of its large gyrencephalic brain, body weight of 70-100 kg, long lifespan, and anatomical, physiological and metabolic resemblance to humans. The Libechov transgenic minipig model for HD (TgHD) has proven useful for proof of concept of developing new therapies. However, to evaluate the efficacy of different therapies on disease progression, a broader phenotypic characterization of the TgHD minipig is needed. In this study, we analyzed the brain tissues of TgHD minipigs at the age of 48 and 60-70 months, and compared them to wild-type animals. We were able to demonstrate not only an accumulation of different forms of mutant huntingtin (mHTT) in TgHD brain, but also pathological changes associated with cellular damage caused by mHTT. At 48 months, we detected pathological changes that included the demyelination of brain white matter, loss of function of striatal neurons in the putamen and activation of microglia. At 60-70 months, we found a clear marker of neurodegeneration: significant cell loss detected in the caudate nucleus, putamen and cortex. This was accompanied by clusters of structures accumulating in the neurites of some neurons, a sign of their degeneration that is also seen in Alzheimer's disease, and a significant activation of astrocytes. In summary, our data demonstrate age-dependent neuropathology with later onset of neurodegeneration in TgHD minipigs.

• Klíčová slova
• Brain, Huntingtin, Large animal model, Neuropathology, TgHD,
• MeSH
• bílá hmota patologie   ultrastruktura   MeSH
• biologické markery metabolismus   MeSH
• degenerace nervu patologie   MeSH
• geneticky modifikovaná zvířata MeSH
• genotyp MeSH
• hmotnostní úbytek MeSH
• Huntingtonova nemoc patologie   MeSH
• index tělesné hmotnosti MeSH
• lidé MeSH
• miniaturní prasata MeSH
• modely nemocí na zvířatech MeSH
• motorické korové centrum patologie   ultrastruktura   MeSH
• myelinová pochva metabolismus   MeSH
• nucleus caudatus patologie   ultrastruktura   MeSH
• prasata MeSH
• protein huntingtin metabolismus   MeSH
• proteinové agregáty MeSH
• stárnutí patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• Htt protein, mouse MeSH Prohlížeč
• protein huntingtin MeSH
• proteinové agregáty MeSH

Skeletal muscle wasting and atrophy is one of the more severe clinical impairments resulting from the progression of Huntington's disease (HD). Mitochondrial dysfunction may play a significant role in the etiology of HD, but the specific condition of mitochondria in muscle has not been widely studied during the development of HD. To determine the role of mitochondria in skeletal muscle during the early stages of HD, we analyzed quadriceps femoris muscle from 24-, 36-, 48- and 66-month-old transgenic minipigs that expressed the N-terminal portion of mutated human huntingtin protein (TgHD) and age-matched wild-type (WT) siblings. We found altered ultrastructure of TgHD muscle tissue and mitochondria. There was also significant reduction of activity of citrate synthase and respiratory chain complexes (RCCs) I, II and IV, decreased quantity of oligomycin-sensitivity conferring protein (OSCP) and the E2 subunit of pyruvate dehydrogenase (PDHE2), and differential expression of optic atrophy 1 protein (OPA1) and dynamin-related protein 1 (DRP1) in the skeletal muscle of TgHD minipigs. Statistical analysis identified several parameters that were dependent only on HD status and could therefore be used as potential biomarkers of disease progression. In particular, the reduction of biomarker RCCII subunit SDH30 quantity suggests that similar pathogenic mechanisms underlie disease progression in TgHD minipigs and HD patients. The perturbed biochemical phenotype was detectable in TgHD minipigs prior to the development of ultrastructural changes and locomotor impairment, which become evident at the age of 48 months. Mitochondrial disturbances may contribute to energetic depression in skeletal muscle in HD, which is in concordance with the mobility problems observed in this model.This article has an associated First Person interview with the first author of the paper.

• Klíčová slova
• Biomarkers, Disease development, HD large animal model, Huntington's disease, Mitochondrial function, Skeletal muscle, Ultrastructure,
• MeSH
• DNA metabolismus   MeSH
• energetický metabolismus * MeSH
• geneticky modifikovaná zvířata MeSH
• Huntingtonova nemoc metabolismus   patologie   MeSH
• kosterní svaly metabolismus   ultrastruktura   MeSH
• lidé MeSH
• miniaturní prasata MeSH
• mitochondriální proteiny metabolismus   MeSH
• modely nemocí na zvířatech * MeSH
• mutace MeSH
• oxidativní fosforylace MeSH
• prasata MeSH
• progrese nemoci MeSH
• protein huntingtin genetika   MeSH
• svalové mitochondrie metabolismus   ultrastruktura   MeSH
• tělesná hmotnost MeSH
• transport elektronů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA MeSH
• HTT protein, human MeSH Prohlížeč
• mitochondriální proteiny MeSH
• protein huntingtin MeSH

Huntington'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.

• Klíčová slova
• DNA damage, DNA repair, HD large animal model, Huntington's disease, Mitochondrial function,
• MeSH
• 8-hydroxy-2'-deoxyguanosin MeSH
• chování zvířat * MeSH
• degenerace nervu patologie   MeSH
• deoxyguanosin analogy a deriváty   metabolismus   MeSH
• energetický metabolismus MeSH
• geneticky modifikovaná zvířata MeSH
• genom MeSH
• Huntingtonova nemoc metabolismus   patologie   MeSH
• lidé MeSH
• miniaturní prasata MeSH
• mitochondrie metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• oprava DNA MeSH
• orgánová specificita MeSH
• poškození DNA MeSH
• prasata MeSH
• protein huntingtin metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 8-hydroxy-2'-deoxyguanosin MeSH
• deoxyguanosin MeSH
• protein huntingtin MeSH