RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory.

Autor:	Sinkevicius KW; Preclinical Pharmacology, Alexion Pharmaceuticals, Lexington, MA 02421, USA., Morrison TR; Center for Translational Neuroimaging, Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA., Kulkarni P; Center for Translational Neuroimaging, Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA., Caffrey Cagliostro MK; Division of Developmental Neuroscience, Department of Psychiatry, Columbia University, New York, NY 10032, USA., Iriah S; Center for Translational Neuroimaging, Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA., Malmberg S; Center for Translational Neuroimaging, Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA., Sabrick J; Center for Translational Neuroimaging, Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA., Honeycutt JA; Center for Translational Neuroimaging, Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA., Askew KL; Preclinical Pharmacology, Alexion Pharmaceuticals, Lexington, MA 02421, USA., Trivedi M; Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33314, USA., Ferris CF; Center for Translational Neuroimaging, Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA c.ferris@northeastern.edu.
Jazyk:	angličtina
Zdroj:	Disease models & mechanisms [Dis Model Mech] 2018 Jun 27; Vol. 11 (6). Date of Electronic Publication: 2018 Jun 27.
DOI:	10.1242/dmm.032631
Abstrakt:	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. Competing Interests: Competing interestsAlexion Pharmaceuticals provided the funding for this study. K.W.S. and K.L.A. are former Alexion Pharmaceuticals employees with equity ownership in Alexion Pharmaceuticals. C.F.F. has a financial interest in Animal Imaging Research, the company that produces the radiofrequency electronics and holders for animal imaging. (© 2018. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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