Behavioral Phenotyping in a Murine Model of <i>GBA1</i>-Associated Parkinson Disease
Mutations in <i>GBA1</i>, the gene encoding glucocerebrosidase, are common genetic risk factors for Parkinson disease (PD). While the mechanism underlying this relationship is unclear, patients with <i>GBA1</i>-associated PD often have an earlier onset and faster progression...
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MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
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| author | Jenny Do Gani Perez Bahafta Berhe Nahid Tayebi Ellen Sidransky |
| author_facet | Jenny Do Gani Perez Bahafta Berhe Nahid Tayebi Ellen Sidransky |
| author_sort | Jenny Do |
| collection | DOAJ |
| description | Mutations in <i>GBA1</i>, the gene encoding glucocerebrosidase, are common genetic risk factors for Parkinson disease (PD). While the mechanism underlying this relationship is unclear, patients with <i>GBA1</i>-associated PD often have an earlier onset and faster progression than idiopathic PD. Previously, we modeled <i>GBA1</i>-associated PD by crossing <i>gba</i> haploinsufficient mice with mice overexpressing a human mutant α-synuclein transgene (<i>SNCA<sup>A53T</sup></i>), observing an earlier demise, shorter life span and faster symptom progression, although behavioral testing was not performed. To assess whether <i>gba<sup><span style="font-variant: small-caps;">+</span></sup></i><sup><span style="font-variant: small-caps;">/−</span></sup>//<i>SNCA<sup>A53T</sup></i> mice exhibit a prodromal behavioral phenotype, we studied three cardinal PD features: olfactory discrimination, memory dysfunction, and motor function. The longitudinal performance of <i>gba<sup>+</sup></i><sup>/<i>−</i></sup>//<i>SNCA<sup>A53T</sup></i> (<i>n</i> = 8), <i>SNCA<sup>A53T</sup></i> (<i>n</i> = 9), <i>gba<sup>+</sup></i><sup>/<i>−</i></sup> (<i>n</i> = 10) and wildtype (<i>n</i> = 6) mice was evaluated between ages 8 and 23 months using the buried pellet test, novel object recognition test and the beam walk. Fifteen-month-old <i>gba<sup>+</sup></i><sup>/<i>−</i></sup>//<i>SNCA<sup>A53T</sup></i> mice showed more olfactory and motor deficits than wildtype mice. However, differences between <i>gba<sup>+</sup></i><sup>/<i>−</i></sup>//<i>SNCA<sup>A53T</sup></i> and <i>SNCA<sup>A53T</sup></i> mice generally did not reach statistical significance, possibly due to small sample sizes. Furthermore, while <i>gba</i> haploinsufficiency leads to a more rapid demise, this might not result in an earlier prodromal stage, and other factors, including aging, oxidative stress and epigenetics, may contribute to the more fulminant disease course. |
| first_indexed | 2024-03-10T10:03:32Z |
| format | Article |
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| language | English |
| last_indexed | 2024-03-10T10:03:32Z |
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| spelling | doaj.art-5e6338651a9d4578bc4ea985265367ce2023-11-22T01:43:21ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-012213682610.3390/ijms22136826Behavioral Phenotyping in a Murine Model of <i>GBA1</i>-Associated Parkinson DiseaseJenny Do0Gani Perez1Bahafta Berhe2Nahid Tayebi3Ellen Sidransky4Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USAMedical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USAMedical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USAMedical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USAMedical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USAMutations in <i>GBA1</i>, the gene encoding glucocerebrosidase, are common genetic risk factors for Parkinson disease (PD). While the mechanism underlying this relationship is unclear, patients with <i>GBA1</i>-associated PD often have an earlier onset and faster progression than idiopathic PD. Previously, we modeled <i>GBA1</i>-associated PD by crossing <i>gba</i> haploinsufficient mice with mice overexpressing a human mutant α-synuclein transgene (<i>SNCA<sup>A53T</sup></i>), observing an earlier demise, shorter life span and faster symptom progression, although behavioral testing was not performed. To assess whether <i>gba<sup><span style="font-variant: small-caps;">+</span></sup></i><sup><span style="font-variant: small-caps;">/−</span></sup>//<i>SNCA<sup>A53T</sup></i> mice exhibit a prodromal behavioral phenotype, we studied three cardinal PD features: olfactory discrimination, memory dysfunction, and motor function. The longitudinal performance of <i>gba<sup>+</sup></i><sup>/<i>−</i></sup>//<i>SNCA<sup>A53T</sup></i> (<i>n</i> = 8), <i>SNCA<sup>A53T</sup></i> (<i>n</i> = 9), <i>gba<sup>+</sup></i><sup>/<i>−</i></sup> (<i>n</i> = 10) and wildtype (<i>n</i> = 6) mice was evaluated between ages 8 and 23 months using the buried pellet test, novel object recognition test and the beam walk. Fifteen-month-old <i>gba<sup>+</sup></i><sup>/<i>−</i></sup>//<i>SNCA<sup>A53T</sup></i> mice showed more olfactory and motor deficits than wildtype mice. However, differences between <i>gba<sup>+</sup></i><sup>/<i>−</i></sup>//<i>SNCA<sup>A53T</sup></i> and <i>SNCA<sup>A53T</sup></i> mice generally did not reach statistical significance, possibly due to small sample sizes. Furthermore, while <i>gba</i> haploinsufficiency leads to a more rapid demise, this might not result in an earlier prodromal stage, and other factors, including aging, oxidative stress and epigenetics, may contribute to the more fulminant disease course.https://www.mdpi.com/1422-0067/22/13/6826Gaucher disease<i>GBA1</i>Parkinson diseasemouse modelburied pellet testnovel object recognition |
| spellingShingle | Jenny Do Gani Perez Bahafta Berhe Nahid Tayebi Ellen Sidransky Behavioral Phenotyping in a Murine Model of <i>GBA1</i>-Associated Parkinson Disease International Journal of Molecular Sciences Gaucher disease <i>GBA1</i> Parkinson disease mouse model buried pellet test novel object recognition |
| title | Behavioral Phenotyping in a Murine Model of <i>GBA1</i>-Associated Parkinson Disease |
| title_full | Behavioral Phenotyping in a Murine Model of <i>GBA1</i>-Associated Parkinson Disease |
| title_fullStr | Behavioral Phenotyping in a Murine Model of <i>GBA1</i>-Associated Parkinson Disease |
| title_full_unstemmed | Behavioral Phenotyping in a Murine Model of <i>GBA1</i>-Associated Parkinson Disease |
| title_short | Behavioral Phenotyping in a Murine Model of <i>GBA1</i>-Associated Parkinson Disease |
| title_sort | behavioral phenotyping in a murine model of i gba1 i associated parkinson disease |
| topic | Gaucher disease <i>GBA1</i> Parkinson disease mouse model buried pellet test novel object recognition |
| url | https://www.mdpi.com/1422-0067/22/13/6826 |
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