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.

Department of Cell Biology Faculty of Science Charles University Prague 128 00 Prague Czech Republic

Department of Circuit Theory Faculty of Electrical Engineering Czech Technical University Prague 166 27 Prague Czech Republic

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine Charles University Prague and General University Hospital Prague 128 21 Prague Czech Republic

Laboratory of Cell Regeneration and Plasticity Institute of Animal Physiology and Genetics Czech Academy of Sciences 277 21 Libechov Czech Republic

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Ardan T., Baxa M., Levinská B., Sedláčková M., Nguyen T. D., Klíma J., Juhás Š., Juhásová J., Šmatlíková P., Vochozková P. et al. (2020). Transgenic minipig model of Huntington's disease exhibiting gradually progressing neurodegeneration. Dis. Model. Mech. 13, dmm.041319 10.1242/dmm.041319 PubMed DOI PMC

Askeland G., Rodinova M., Štufková H., Dosoudilova Z., Baxa M., Smatlikova P., Bohuslavova B., Klempir J., Nguyen T. D., Kuśnierczyk A. et al. (2018). A transgenic minipig model of Huntington's disease shows early signs of behavioral and molecular pathologies. Dis. Model. Mech. 11, dmm035949 10.1242/dmm.035949 PubMed DOI PMC

Baxa M., Hruska-Plochan M., Juhas S., Vodicka P., Pavlok A., Juhasova J., Miyanohara A., Nejime T., Klima J., Macakova M. et al. (2013). A transgenic minipig model of Huntington's disease. J. Huntington's Dis. 2, 47-68. 10.3233/JHD-130001 PubMed DOI

Beighton P. and Hayden M. R. (1981). Huntington's chorea. S. Afr. Med. J. 59, 250. PubMed

Beraldi R., Chan C.-H., Rogers C. S., Kovács A. D., Meyerholz D. K., Trantzas C., Lambertz A. M., Darbro B. W., Weber K. L., White K. A. M. et al. (2015). A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease. Hum. Mol. Genet. 24, 6473-6484. 10.1093/hmg/ddv356 PubMed DOI PMC

Brandt J., Strauss M. E., Larus J., Jensen B., Folstein S. E. and Folstein M. F. (1984). Clinical correlates of dementia and disability in Huntington's disease. J. Clin. Neuropsychol. 6, 401-412. 10.1080/01688638408401231 PubMed DOI

Cahill L. (2014). Fundamental sex difference in human brain architecture. Proc. Natl. Acad. Sci. USA 111, 577-578. 10.1073/pnas.1320954111 PubMed DOI PMC

Caron N. S., Wright G. E. and Hayden M. R. (1993). Huntington disease GeneReviews® [Internet] (ed. M. P. Adam, H. H. Ardinger, R. A. Pagon et al.). University of Washington, Seattle; 1993-2019.

David A. S., Jeste D. V., Folstein M. F. and Folstein S. E. (1987). Voluntary movement dysfunction in Huntington's disease and tardive dyskinesia. Acta Neurol. Scand. 75, 130-139. 10.1111/j.1600-0404.1987.tb07907.x PubMed DOI

Dumas E., van den Bogaard S., Middelkoop H. and Roos R. (2013). A review of cognition in Huntington's disease. Front. Biosci. (Schol. Ed.) 5, 1-18. 10.2741/S355 PubMed DOI

Eddy C. M., Parkinson E. G. and Rickards H. E. (2016). Changes in mental state and behaviour in Huntington's disease. Lancet Psychiatry 3, 1079-1086. 10.1016/S2215-0366(16)30144-4 PubMed DOI

Evers M. M., Miniarikova J., Juhas S., Vallès A., Bohuslavova B., Juhasova J., Skalnikova H. K., Vodicka P., Valekova I., Brouwers C. et al. (2018). AAV5-miHTT gene therapy demonstrates broad distribution and strong human mutant huntingtin lowering in a Huntington's disease minipig model. Mol. Ther. 26, 2163-2177. 10.1016/j.ymthe.2018.06.021 PubMed DOI PMC

Herzog-Krzywoszanska R. and Krzywoszanski L. (2019). Sleep disorders in Huntington's disease. Front. Psychiatry 10, 221 10.3389/fpsyt.2019.00221 PubMed DOI PMC

Howland D. S. and Munoz-Sanjuan I. (2014). Mind the gap: models in multiple species needed for therapeutic development in Huntington's disease. Mov. Disord. 29, 1397-1403. 10.1002/mds.26008 PubMed DOI

Huntington Study Group (1996). Unified Huntington's disease rating scale: reliability and consistency. Mov. Disord. 11, 136-142. 10.1002/mds.870110204 PubMed DOI

Jacobsen J. C., Bawden C. S., Rudiger S. R., McLaughlan C. J., Reid S. J., Waldvogel H. J., MacDonald M. E., Gusella J. F., Walker S. K., Kelly J. M. et al. (2010). An ovine transgenic Huntington's disease model. Hum. Mol. Genet. 19, 1873-1882. 10.1093/hmg/ddq063 PubMed DOI PMC

Kocerha J., Liu Y., Willoughby D., Chidamparam K., Benito J., Nelson K., Xu Y., Chi T., Engelhardt H., Moran S. et al. (2013). Longitudinal transcriptomic dysregulation in the peripheral blood of transgenic Huntington's disease monkeys. BMC Neurosci. 14, 88 10.1186/1471-2202-14-88 PubMed DOI PMC

Krizova J., Stufkova H., Rodinova M., Macakova M., Bohuslavova B., Vidinska D., Klima J., Ellederova Z., Pavlok A., Howland D. S. et al. (2017). Mitochondrial metabolism in a large-animal model of Huntington disease: the hunt for biomarkers in the spermatozoa of presymptomatic minipigs. Neurodegener. Dis. 17, 213-226. 10.1159/000475467 PubMed DOI

Kudo T., Schroeder A., Loh D. H., Kuljis D., Jordan M. C., Roos K. P. and Colwell C. S. (2011). Dysfunctions in circadian behavior and physiology in mouse models of Huntington's disease. Exp. Neurol. 228, 80-90. 10.1016/j.expneurol.2010.12.011 PubMed DOI PMC

Lai J.-S., Goodnight S., Downing N. R., Ready R. E., Paulsen J. S., Kratz A. L., Stout J. C., McCormack M. K., Cella D., Ross C. et al. (2018). Evaluating cognition in individuals with Huntington disease: neuro-qol cognitive functioning measures. Qual. Life Res. 27, 811-822. 10.1007/s11136-017-1755-6 PubMed DOI PMC

Lee J. K., Ding Y., Conrad A. L., Cattaneo E., Epping E., Mathews K., Gonzalez-Alegre P., Cahill L., Magnotta V., Schlaggar B. L. et al. (2017). Sex-specific effects of the Huntington gene on normal neurodevelopment. J. Neurosci. Res. 95, 398-408. 10.1002/jnr.23980 PubMed DOI PMC

Macakova M., Bohuslavova B., Vochozkova P., Pavlok A., Sedlackova M., Vidinska D., Vochyanova K., Liskova I., Valekova I., Baxa M. et al. (2016). Mutated Huntingtin causes testicular pathology in transgenic minipig boars. Neurodegener. Dis. 16, 245-259. 10.1159/000443665 PubMed DOI

Marino L. and Colvin C. M. (2015). Thinking Pigs: A Comparative Review of Cognition, Emotion, and Personality in Sus domesticus Int. J. Comp. Psych. 28.

McBride S. D., Perentos N. and Morton A. J. (2016). A mobile, high-throughput semi-automated system for testing cognition in large non-primate animal models of Huntington disease. J. Neurosci. Methods 265, 25-33. 10.1016/j.jneumeth.2015.08.025 PubMed DOI

Morton A. J. and Howland D. S. (2013). Large genetic animal models of Huntington's disease. J. Huntington's Dis. 2, 3-19. 10.3233/JHD-130050 PubMed DOI

Morton A. J., Wood N. I., Hastings M. H., Hurelbrink C., Barker R. A. and Maywood E. S. (2005). Disintegration of the sleep-wake cycle and circadian timing in Huntington's disease. J. Neurosci. 25, 157-163. 10.1523/JNEUROSCI.3842-04.2005 PubMed DOI PMC

Nance M. A. (1998). Huntington disease: clinical, genetic, and social aspects. J. Geriatr. Psychiatry Neurol. 11, 61-70. 10.1177/089198879801100204 PubMed DOI

Pokorný M., Juhás S., Juhásová J., Klíma J., Motlík J., Klempíř J. and Havlík J. (2015). Telemetry physical activity monitoring in minipig's model of Huntington's disease. Cesk Slov Neurol N. 78/111 Suppl. 2, 39-42. 10.14735/amcsnn20152S39 DOI

Reilmann R., Bohlen S., Klopstock T., Bender A., Weindl A., Saemann P., Auer D. P., Ringelstein E. B. and Lange H. W. (2010). Tongue force analysis assesses motor phenotype in premanifest and symptomatic Huntington's disease. Mov. Disord. 25, 2195-2202. 10.1002/mds.23243 PubMed DOI

Rodinova M., Krizova J., Stufkova H., Bohuslavova B., Askeland G., Dosoudilova Z., Juhas S., Juhasova J., Ellederova Z., Zeman J. et al. (2019). Skeletal muscle in an early manifest transgenic minipig model of Huntington's disease revealed deterioration of mitochondrial bioenergetics and ultrastructure impairment. Dis. Model. Mech. 12, dmm038737 10.1242/dmm.038737 PubMed DOI PMC

Rüb U., Hoche F., Brunt E. R., Heinsen H., Seidel K., Del Turco D., Paulson H. L., Bohl J., von Gall C., Vonsattel J.-P. et al. (2013). Degeneration of the cerebellum in Huntington's disease (HD): possible relevance for the clinical picture and potential gateway to pathological mechanisms of the disease process. Brain Pathol. 23, 165-177. 10.1111/j.1750-3639.2012.00629.x PubMed DOI PMC

Schramke S., Schuldenzucker V., Schubert R., Frank F., Wirsig M., Ott S., Motlik J., Fels M., Kemper N., Hölzner E. et al. (2016). Behavioral phenotyping of minipigs transgenic for the Huntington gene. J. Neurosci. Methods 265, 34-45. 10.1016/j.jneumeth.2015.11.013 PubMed DOI

Schuldenzucker V., Schubert R., Muratori L. M., Freisfeld F., Rieke L., Matheis T., Schramke S., Motlik J., Kemper N., Radespiel U. et al. (2017). Behavioral testing of minipigs transgenic for the Huntington gene—A three-year observational study. PLoS ONE 12, e0185970 10.1371/journal.pone.0185970 PubMed DOI PMC

Smith M. A., Brandt J. and Shadmehr R. (2000). Motor disorder in Huntington's disease begins as a dysfunction in error feedback control. Nature 403, 544-549. 10.1038/35000576 PubMed DOI PMC

Trejo A., Tarrats R. M., Alonso M. E., Boll M.-C., Ochoa A. and Velásquez L. (2004). Assessment of the nutrition status of patients with Huntington's disease. Nutrition 20, 192-196. 10.1016/j.nut.2003.10.007 PubMed DOI

Uchida M., Shimatsu Y., Onoe K., Matsuyama N., Niki R., Ikeda J.-E. and Imai H. (2001). Production of transgenic miniature pigs by pronuclear microinjection. Transgenic Res. 10, 577-582. 10.1023/A:1013059917280 PubMed DOI

Vidinská D., Vochozková P., Šmatlíková P., Ardan T., Klíma J., Juhás S., Juhásová J., Bohuslavová B., Baxa M., Valeková I. et al. (2018). Gradual phenotype development in Huntington disease transgenic minipig model at 24 months of age. Neurodegener. Dis. 18, 107-119. 10.1159/000488592 PubMed DOI

Vodička P., Smetana K. Jr, Dvořánková B., Emerick T., Xu Y. Z., Ourednik J., Ourednik V. and Motlík J. (2005). The miniature pig as an animal model in biomedical research. Ann. N. Y. Acad. Sci. 1049, 161-171. 10.1196/annals.1334.015 PubMed DOI

Vuong K., Canning C. G., Menant J. C. and Loy C. T. (2018). Gait, balance, and falls in Huntington disease. Handb. Clin. Neurol. 159, 251-260. 10.1016/B978-0-444-63916-5.00016-1 PubMed DOI

Yan S., Tu Z., Liu Z., Fan N., Yang H., Yang S., Yang W., Zhao Y., Ouyang Z., Lai C. et al. (2018). A Huntingtin knockin pig model recapitulates features of selective neurodegeneration in Huntington's disease. Cell 173, 989-1002.e13. 10.1016/j.cell.2018.03.005 PubMed DOI PMC

Yang S.-H., Cheng P.-H., Banta H., Piotrowska-Nitsche K., Yang J.-J., Cheng E. C. H., Snyder B., Larkin K., Liu J., Orkin J. et al. (2008). Towards a transgenic model of Huntington's disease in a non-human primate. Nature 453, 921-924. 10.1038/nature06975 PubMed DOI PMC

Yang D., Wang C.-E., Zhao B., Li W., Ouyang Z., Liu Z., Yang H., Fan P., O'Neill A., Gu W. et al. (2010). Expression of Huntington's disease protein results in apoptotic neurons in the brains of cloned transgenic pigs. Hum. Mol. Genet. 19, 3983-3994. 10.1093/hmg/ddq313 PubMed DOI PMC

Huntingtin Co-Isolates with Small Extracellular Vesicles from Blood Plasma of TgHD and KI-HD Pig Models of Huntington's Disease and Human Blood Plasma