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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...

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Autores principales: Sinkevicius, Kerstin W., Morrison, Thomas R., Kulkarni, Praveen, Caffrey Cagliostro, Martha K., Iriah, Sade, Malmberg, Samantha, Sabrick, Julia, Honeycutt, Jennifer A., Askew, Kim L., Trivedi, Malav, Ferris, Craig F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031352/
https://www.ncbi.nlm.nih.gov/pubmed/29752287
http://dx.doi.org/10.1242/dmm.032631
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author Sinkevicius, Kerstin W.
Morrison, Thomas R.
Kulkarni, Praveen
Caffrey Cagliostro, Martha K.
Iriah, Sade
Malmberg, Samantha
Sabrick, Julia
Honeycutt, Jennifer A.
Askew, Kim L.
Trivedi, Malav
Ferris, Craig F.
author_facet Sinkevicius, Kerstin W.
Morrison, Thomas R.
Kulkarni, Praveen
Caffrey Cagliostro, Martha K.
Iriah, Sade
Malmberg, Samantha
Sabrick, Julia
Honeycutt, Jennifer A.
Askew, Kim L.
Trivedi, Malav
Ferris, Craig F.
author_sort Sinkevicius, Kerstin W.
collection PubMed
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.
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spelling pubmed-60313522018-07-06 RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory Sinkevicius, Kerstin W. Morrison, Thomas R. Kulkarni, Praveen Caffrey Cagliostro, Martha K. Iriah, Sade Malmberg, Samantha Sabrick, Julia Honeycutt, Jennifer A. Askew, Kim L. Trivedi, Malav Ferris, Craig F. Dis Model Mech Research Article 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. The Company of Biologists Ltd 2018-06-01 2018-06-27 /pmc/articles/PMC6031352/ /pubmed/29752287 http://dx.doi.org/10.1242/dmm.032631 Text en © 2018. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Sinkevicius, Kerstin W.
Morrison, Thomas R.
Kulkarni, Praveen
Caffrey Cagliostro, Martha K.
Iriah, Sade
Malmberg, Samantha
Sabrick, Julia
Honeycutt, Jennifer A.
Askew, Kim L.
Trivedi, Malav
Ferris, Craig F.
RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory
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 Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031352/
https://www.ncbi.nlm.nih.gov/pubmed/29752287
http://dx.doi.org/10.1242/dmm.032631
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