Ocular phenotypes in a mouse model of impaired glucocerebrosidase activity
Abstract Mutations in the GBA1 gene encoding glucocerebrosidase (GCase) are linked to Gaucher (GD) and Parkinson’s Disease (PD). Since some GD and PD patients develop ocular phenotypes, we determined whether ocular phenotypes might result from impaired GCase activity and the corresponding accumulati...
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Nature Portfolio
2021
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oai:doaj.org-article:08dc67cbf02f4f9ab4c713dcac4d08672021-12-02T17:04:53ZOcular phenotypes in a mouse model of impaired glucocerebrosidase activity10.1038/s41598-021-85528-42045-2322https://doaj.org/article/08dc67cbf02f4f9ab4c713dcac4d08672021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85528-4https://doaj.org/toc/2045-2322Abstract Mutations in the GBA1 gene encoding glucocerebrosidase (GCase) are linked to Gaucher (GD) and Parkinson’s Disease (PD). Since some GD and PD patients develop ocular phenotypes, we determined whether ocular phenotypes might result from impaired GCase activity and the corresponding accumulation of glucosylceramide (GluCer) and glucosylsphingosine (GluSph) in the Gba1 D409V/D409V knock-in (Gba KI/KI; “KI”) mouse. Gba KI mice developed age-dependent pupil dilation deficits to an anti-muscarinic agent; histologically, the iris covered the anterior part of the lens with adhesions between the iris and the anterior surface of the lens (posterior synechia). This may prevent pupil dilation in general, beyond an un-responsiveness of the iris to anti-muscarinics. Gba KI mice displayed atrophy and pigment dispersion of the iris, and occlusion of the iridocorneal angle by pigment-laden cells, reminiscent of secondary open angle glaucoma. Gba KI mice showed progressive thinning of the retina consistent with retinal degeneration. GluSph levels were increased in the anterior and posterior segments of the eye, suggesting that accumulation of lipids in the eye may contribute to degeneration in this compartment. We conclude that the Gba KI model provides robust and reproducible eye phenotypes which may be used to test for efficacy and establish biomarkers for GBA1-related therapies.Martin WeberSang-Won MinTom TruongJeffrey HungStephanie DaleMike ReicheltSavita UbhayakarCarol Cain-HomMiriam BacaZhiyu JiangQingling LiRobert BrendzaHan LinChung KungWilliam F. ForrestCristine Quiason-HuynhWendy SandovalBuyun ChenYuzhong DengAmy EastonOded ForemanAbdoulaye SeneBaris BingolNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021) |
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Medicine R Science Q Martin Weber Sang-Won Min Tom Truong Jeffrey Hung Stephanie Dale Mike Reichelt Savita Ubhayakar Carol Cain-Hom Miriam Baca Zhiyu Jiang Qingling Li Robert Brendza Han Lin Chung Kung William F. Forrest Cristine Quiason-Huynh Wendy Sandoval Buyun Chen Yuzhong Deng Amy Easton Oded Foreman Abdoulaye Sene Baris Bingol Ocular phenotypes in a mouse model of impaired glucocerebrosidase activity |
| description |
Abstract Mutations in the GBA1 gene encoding glucocerebrosidase (GCase) are linked to Gaucher (GD) and Parkinson’s Disease (PD). Since some GD and PD patients develop ocular phenotypes, we determined whether ocular phenotypes might result from impaired GCase activity and the corresponding accumulation of glucosylceramide (GluCer) and glucosylsphingosine (GluSph) in the Gba1 D409V/D409V knock-in (Gba KI/KI; “KI”) mouse. Gba KI mice developed age-dependent pupil dilation deficits to an anti-muscarinic agent; histologically, the iris covered the anterior part of the lens with adhesions between the iris and the anterior surface of the lens (posterior synechia). This may prevent pupil dilation in general, beyond an un-responsiveness of the iris to anti-muscarinics. Gba KI mice displayed atrophy and pigment dispersion of the iris, and occlusion of the iridocorneal angle by pigment-laden cells, reminiscent of secondary open angle glaucoma. Gba KI mice showed progressive thinning of the retina consistent with retinal degeneration. GluSph levels were increased in the anterior and posterior segments of the eye, suggesting that accumulation of lipids in the eye may contribute to degeneration in this compartment. We conclude that the Gba KI model provides robust and reproducible eye phenotypes which may be used to test for efficacy and establish biomarkers for GBA1-related therapies. |
| format |
article |
| author |
Martin Weber Sang-Won Min Tom Truong Jeffrey Hung Stephanie Dale Mike Reichelt Savita Ubhayakar Carol Cain-Hom Miriam Baca Zhiyu Jiang Qingling Li Robert Brendza Han Lin Chung Kung William F. Forrest Cristine Quiason-Huynh Wendy Sandoval Buyun Chen Yuzhong Deng Amy Easton Oded Foreman Abdoulaye Sene Baris Bingol |
| author_facet |
Martin Weber Sang-Won Min Tom Truong Jeffrey Hung Stephanie Dale Mike Reichelt Savita Ubhayakar Carol Cain-Hom Miriam Baca Zhiyu Jiang Qingling Li Robert Brendza Han Lin Chung Kung William F. Forrest Cristine Quiason-Huynh Wendy Sandoval Buyun Chen Yuzhong Deng Amy Easton Oded Foreman Abdoulaye Sene Baris Bingol |
| author_sort |
Martin Weber |
| title |
Ocular phenotypes in a mouse model of impaired glucocerebrosidase activity |
| title_short |
Ocular phenotypes in a mouse model of impaired glucocerebrosidase activity |
| title_full |
Ocular phenotypes in a mouse model of impaired glucocerebrosidase activity |
| title_fullStr |
Ocular phenotypes in a mouse model of impaired glucocerebrosidase activity |
| title_full_unstemmed |
Ocular phenotypes in a mouse model of impaired glucocerebrosidase activity |
| title_sort |
ocular phenotypes in a mouse model of impaired glucocerebrosidase activity |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/08dc67cbf02f4f9ab4c713dcac4d0867 |
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