RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory
RNASET2 deficiency in humans is associated with infant cystic leukoencephalopathy, which causes psychomotor impairment, spasticity and epilepsy. A zebrafish mutant model suggests that loss of RNASET2 function leads to neurodegeneration due to the accumulation of non-degraded RNA in the lysosomes. Th...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
The Company of Biologists
2018-06-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/11/6/dmm032631 |
| _version_ | 1818528199040040960 |
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| author | Kerstin W. Sinkevicius Thomas R. Morrison Praveen Kulkarni Martha K. Caffrey Cagliostro Sade Iriah Samantha Malmberg Julia Sabrick Jennifer A. Honeycutt Kim L. Askew Malav Trivedi Craig F. Ferris |
| author_facet | Kerstin W. Sinkevicius Thomas R. Morrison Praveen Kulkarni Martha K. Caffrey Cagliostro Sade Iriah Samantha Malmberg Julia Sabrick Jennifer A. Honeycutt Kim L. Askew Malav Trivedi Craig F. Ferris |
| author_sort | Kerstin W. Sinkevicius |
| collection | DOAJ |
| description | RNASET2 deficiency in humans is associated with infant cystic leukoencephalopathy, which causes psychomotor impairment, spasticity and epilepsy. A zebrafish mutant model suggests that loss of RNASET2 function leads to neurodegeneration due to the accumulation of non-degraded RNA in the lysosomes. The goal of this study was to characterize the first rodent model of RNASET2 deficiency. The brains of 3- and 12-month-old RNaseT2 knockout rats were studied using multiple magnetic resonance imaging modalities and behavioral tests. While T1- and T2-weighted images of RNaseT2 knockout rats exhibited no evidence of cystic lesions, the prefrontal cortex and hippocampal complex were enlarged in knockout animals. Diffusion-weighted imaging showed altered anisotropy and putative gray matter changes in the hippocampal complex of the RNaseT2 knockout rats. Immunohistochemistry for glial fibrillary acidic protein (GFAP) showed the presence of hippocampal neuroinflammation. Decreased levels of lysosome-associated membrane protein 2 (LAMP2) and elevated acid phosphatase and β-N-acetylglucosaminidase (NAG) activities indicated that the RNASET2 knockout rats likely had altered lysosomal function and potential defects in autophagy. Object recognition tests confirmed that RNaseT2 knockout rats exhibited memory deficits. However, the Barnes maze, and balance beam and rotarod tests indicated there were no differences in spatial memory or motor impairments, respectively. Overall, patients with RNASET2 deficiency exhibited a more severe neurodegeneration phenotype than was observed in the RNaseT2 knockout rats. However, the vulnerability of the knockout rat hippocampus as evidenced by neuroinflammation, altered lysosomal function and cognitive defects indicates that this is still a useful in vivo model to study RNASET2 function. |
| first_indexed | 2024-12-11T06:46:34Z |
| format | Article |
| id | doaj.art-b9842a2e8fc9477ea34b7dd94fe4f39e |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-11T06:46:34Z |
| publishDate | 2018-06-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-b9842a2e8fc9477ea34b7dd94fe4f39e2022-12-22T01:17:03ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112018-06-0111610.1242/dmm.032631032631RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memoryKerstin W. Sinkevicius0Thomas R. Morrison1Praveen Kulkarni2Martha K. Caffrey Cagliostro3Sade Iriah4Samantha Malmberg5Julia Sabrick6Jennifer A. Honeycutt7Kim L. Askew8Malav Trivedi9Craig F. Ferris10 Preclinical Pharmacology, Alexion Pharmaceuticals, Lexington, MA 02421, USA Center for Translational Neuroimaging, Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA Center for Translational Neuroimaging, Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA Division of Developmental Neuroscience, Department of Psychiatry, Columbia University, New York, NY 10032, USA Center for Translational Neuroimaging, Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA Center for Translational Neuroimaging, Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA Center for Translational Neuroimaging, Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA Center for Translational Neuroimaging, Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA Preclinical Pharmacology, Alexion Pharmaceuticals, Lexington, MA 02421, USA Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33314, USA Center for Translational Neuroimaging, Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA RNASET2 deficiency in humans is associated with infant cystic leukoencephalopathy, which causes psychomotor impairment, spasticity and epilepsy. A zebrafish mutant model suggests that loss of RNASET2 function leads to neurodegeneration due to the accumulation of non-degraded RNA in the lysosomes. The goal of this study was to characterize the first rodent model of RNASET2 deficiency. The brains of 3- and 12-month-old RNaseT2 knockout rats were studied using multiple magnetic resonance imaging modalities and behavioral tests. While T1- and T2-weighted images of RNaseT2 knockout rats exhibited no evidence of cystic lesions, the prefrontal cortex and hippocampal complex were enlarged in knockout animals. Diffusion-weighted imaging showed altered anisotropy and putative gray matter changes in the hippocampal complex of the RNaseT2 knockout rats. Immunohistochemistry for glial fibrillary acidic protein (GFAP) showed the presence of hippocampal neuroinflammation. Decreased levels of lysosome-associated membrane protein 2 (LAMP2) and elevated acid phosphatase and β-N-acetylglucosaminidase (NAG) activities indicated that the RNASET2 knockout rats likely had altered lysosomal function and potential defects in autophagy. Object recognition tests confirmed that RNaseT2 knockout rats exhibited memory deficits. However, the Barnes maze, and balance beam and rotarod tests indicated there were no differences in spatial memory or motor impairments, respectively. Overall, patients with RNASET2 deficiency exhibited a more severe neurodegeneration phenotype than was observed in the RNaseT2 knockout rats. However, the vulnerability of the knockout rat hippocampus as evidenced by neuroinflammation, altered lysosomal function and cognitive defects indicates that this is still a useful in vivo model to study RNASET2 function.http://dmm.biologists.org/content/11/6/dmm032631Diffusion-weighted imagingMagnetic resonance imagingCRISPR/Cas9Lysosomal storage diseaseObject recognitionGlial fibrillary acidic protein |
| spellingShingle | Kerstin W. Sinkevicius Thomas R. Morrison Praveen Kulkarni Martha K. Caffrey Cagliostro Sade Iriah Samantha Malmberg Julia Sabrick Jennifer A. Honeycutt Kim L. Askew Malav Trivedi Craig F. Ferris RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory Disease Models & Mechanisms Diffusion-weighted imaging Magnetic resonance imaging CRISPR/Cas9 Lysosomal storage disease Object recognition Glial fibrillary acidic protein |
| title | RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory |
| title_full | RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory |
| title_fullStr | RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory |
| title_full_unstemmed | RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory |
| title_short | RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory |
| title_sort | rnaset2 knockout rats exhibit hippocampal neuropathology and deficits in memory |
| topic | Diffusion-weighted imaging Magnetic resonance imaging CRISPR/Cas9 Lysosomal storage disease Object recognition Glial fibrillary acidic protein |
| url | http://dmm.biologists.org/content/11/6/dmm032631 |
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