Rapid and robust patterns of spontaneous locomotor deficits in mouse models of Huntington's disease
Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by severe disruption of cognitive and motor functions, including changes in posture and gait. A number of HD mouse models have been engineered that display behavioral and neuropathological features of the disease...
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| creator | Heikkinen, Taneli Bragge, Timo Bhattarai, Niina Parkkari, Teija Puoliväli, Jukka Kontkanen, Outi Sweeney, Patrick Park, Larry C Munoz-Sanjuan, Ignacio |
| description | Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by severe disruption of cognitive and motor functions, including changes in posture and gait. A number of HD mouse models have been engineered that display behavioral and neuropathological features of the disease, but gait alterations in these models are poorly characterized. Sensitive high-throughput tests of fine motor function and gait in mice might be informative in evaluating disease-modifying interventions. Here, we describe a hypothesis-free workflow that determines progressively changing locomotor patterns across 79 parameters in the R6/2 and Q175 mouse models of HD. R6/2 mice (120 CAG repeats) showed motor disturbances as early as at 4 weeks of age. Similar disturbances were observed in homozygous and heterozygous Q175 KI mice at 3 and 6 months of age, respectively. Interestingly, only the R6/2 mice developed forelimb ataxia. The principal components of the behavioral phenotypes produced two phenotypic scores of progressive postural instability based on kinematic parameters and trajectory waveform data, which were shared by both HD models. This approach adds to the available HD mouse model research toolbox and has a potential to facilitate the development of therapeutics for HD and other debilitating movement disorders with high unmet medical need. |
| doi_str_mv | 10.1371/journal.pone.0243052 |
| format | Article |
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A number of HD mouse models have been engineered that display behavioral and neuropathological features of the disease, but gait alterations in these models are poorly characterized. Sensitive high-throughput tests of fine motor function and gait in mice might be informative in evaluating disease-modifying interventions. Here, we describe a hypothesis-free workflow that determines progressively changing locomotor patterns across 79 parameters in the R6/2 and Q175 mouse models of HD. R6/2 mice (120 CAG repeats) showed motor disturbances as early as at 4 weeks of age. Similar disturbances were observed in homozygous and heterozygous Q175 KI mice at 3 and 6 months of age, respectively. Interestingly, only the R6/2 mice developed forelimb ataxia. The principal components of the behavioral phenotypes produced two phenotypic scores of progressive postural instability based on kinematic parameters and trajectory waveform data, which were shared by both HD models. This approach adds to the available HD mouse model research toolbox and has a potential to facilitate the development of therapeutics for HD and other debilitating movement disorders with high unmet medical need.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0243052</identifier><identifier>PMID: 33370315</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Age ; Animal models ; Animal models in research ; Animals ; Ataxia ; Biology and Life Sciences ; Biomechanical Phenomena ; Cognitive ability ; Disease Models, Animal ; Disturbances ; Drug development ; Female ; Gait ; Gait Analysis - methods ; Genotype & phenotype ; Health aspects ; Huntingtin Protein - genetics ; Huntington Disease - genetics ; Huntington Disease - physiopathology ; Huntington's chorea ; Huntington's disease ; Huntingtons disease ; Kinematics ; Laboratory animals ; Locomotion ; Male ; Mathematical models ; Medicine and Health Sciences ; Mice ; Mice, Transgenic ; Motor Activity ; Movement disorders ; Mutation ; Neurodegenerative diseases ; Parameters ; Phenotypes ; Physical Sciences ; Polyglutamine ; Posture ; Research and Analysis Methods ; Rodents ; Trinucleotide repeats ; Waveforms ; Workflow</subject><ispartof>PloS one, 2020-12, Vol.15 (12), p.e0243052-e0243052</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Heikkinen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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This approach adds to the available HD mouse model research toolbox and has a potential to facilitate the development of therapeutics for HD and other debilitating movement disorders with high unmet medical need.</description><subject>Age</subject><subject>Animal models</subject><subject>Animal models in research</subject><subject>Animals</subject><subject>Ataxia</subject><subject>Biology and Life Sciences</subject><subject>Biomechanical Phenomena</subject><subject>Cognitive ability</subject><subject>Disease Models, Animal</subject><subject>Disturbances</subject><subject>Drug development</subject><subject>Female</subject><subject>Gait</subject><subject>Gait Analysis - methods</subject><subject>Genotype & phenotype</subject><subject>Health aspects</subject><subject>Huntingtin Protein - genetics</subject><subject>Huntington Disease - genetics</subject><subject>Huntington Disease - physiopathology</subject><subject>Huntington's chorea</subject><subject>Huntington's 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and robust patterns of spontaneous locomotor deficits in mouse models of Huntington's disease</title><author>Heikkinen, Taneli ; Bragge, Timo ; Bhattarai, Niina ; Parkkari, Teija ; Puoliväli, Jukka ; Kontkanen, Outi ; Sweeney, Patrick ; Park, Larry C ; Munoz-Sanjuan, Ignacio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-145fa7025ebed47586277b91e5c30a9772ee7252b78f831cb85fd48fc14214003</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Age</topic><topic>Animal models</topic><topic>Animal models in research</topic><topic>Animals</topic><topic>Ataxia</topic><topic>Biology and Life Sciences</topic><topic>Biomechanical Phenomena</topic><topic>Cognitive ability</topic><topic>Disease Models, Animal</topic><topic>Disturbances</topic><topic>Drug development</topic><topic>Female</topic><topic>Gait</topic><topic>Gait Analysis - methods</topic><topic>Genotype & phenotype</topic><topic>Health aspects</topic><topic>Huntingtin Protein - genetics</topic><topic>Huntington Disease - genetics</topic><topic>Huntington Disease - physiopathology</topic><topic>Huntington's chorea</topic><topic>Huntington's disease</topic><topic>Huntingtons disease</topic><topic>Kinematics</topic><topic>Laboratory animals</topic><topic>Locomotion</topic><topic>Male</topic><topic>Mathematical models</topic><topic>Medicine and Health Sciences</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Motor Activity</topic><topic>Movement disorders</topic><topic>Mutation</topic><topic>Neurodegenerative diseases</topic><topic>Parameters</topic><topic>Phenotypes</topic><topic>Physical Sciences</topic><topic>Polyglutamine</topic><topic>Posture</topic><topic>Research and Analysis Methods</topic><topic>Rodents</topic><topic>Trinucleotide 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disease (HD) is an inherited neurodegenerative disorder characterized by severe disruption of cognitive and motor functions, including changes in posture and gait. A number of HD mouse models have been engineered that display behavioral and neuropathological features of the disease, but gait alterations in these models are poorly characterized. Sensitive high-throughput tests of fine motor function and gait in mice might be informative in evaluating disease-modifying interventions. Here, we describe a hypothesis-free workflow that determines progressively changing locomotor patterns across 79 parameters in the R6/2 and Q175 mouse models of HD. R6/2 mice (120 CAG repeats) showed motor disturbances as early as at 4 weeks of age. Similar disturbances were observed in homozygous and heterozygous Q175 KI mice at 3 and 6 months of age, respectively. Interestingly, only the R6/2 mice developed forelimb ataxia. The principal components of the behavioral phenotypes produced two phenotypic scores of progressive postural instability based on kinematic parameters and trajectory waveform data, which were shared by both HD models. This approach adds to the available HD mouse model research toolbox and has a potential to facilitate the development of therapeutics for HD and other debilitating movement disorders with high unmet medical need.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>33370315</pmid><doi>10.1371/journal.pone.0243052</doi><tpages>e0243052</tpages><orcidid>https://orcid.org/0000-0002-8844-6618</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Age Animal models Animal models in research Animals Ataxia Biology and Life Sciences Biomechanical Phenomena Cognitive ability Disease Models, Animal Disturbances Drug development Female Gait Gait Analysis - methods Genotype & phenotype Health aspects Huntingtin Protein - genetics Huntington Disease - genetics Huntington Disease - physiopathology Huntington's chorea Huntington's disease Huntingtons disease Kinematics Laboratory animals Locomotion Male Mathematical models Medicine and Health Sciences Mice Mice, Transgenic Motor Activity Movement disorders Mutation Neurodegenerative diseases Parameters Phenotypes Physical Sciences Polyglutamine Posture Research and Analysis Methods Rodents Trinucleotide repeats Waveforms Workflow |
| title | Rapid and robust patterns of spontaneous locomotor deficits in mouse models of Huntington's disease |
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