Central nervous system pathology in preclinical MPS IIIB dogs reveals progressive changes in clinically relevant brain regions

Abstract Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B) is an autosomal recessive lysosomal storage disorder caused by the deficiency of alpha-N-acetylglucosaminidase activity, leading to increased levels of nondegraded heparan sulfate (HS). A mouse model has been useful to evalua...

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Autores principales:	Martin T. Egeland, Marta M. Tarczyluk-Wells, Melissa M. Asmar, Evan G. Adintori, Roger Lawrence, Elizabeth M. Snella, Jackie K. Jens, Brett E. Crawford, Jill C. M. Wait, Emma McCullagh, Jason Pinkstaff, Jonathan D. Cooper, N. Matthew Ellinwood
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5500192f556445fb9991fe7f6927c244
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spelling	oai:doaj.org-article:5500192f556445fb9991fe7f6927c2442021-12-02T12:34:16ZCentral nervous system pathology in preclinical MPS IIIB dogs reveals progressive changes in clinically relevant brain regions10.1038/s41598-020-77032-y2045-2322https://doaj.org/article/5500192f556445fb9991fe7f6927c2442020-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-77032-yhttps://doaj.org/toc/2045-2322Abstract Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B) is an autosomal recessive lysosomal storage disorder caused by the deficiency of alpha-N-acetylglucosaminidase activity, leading to increased levels of nondegraded heparan sulfate (HS). A mouse model has been useful to evaluate novel treatments for MPS IIIB, but has limitations. In this study, we evaluated the naturally occurring canine model of MPS IIIB for the onset and progression of biochemical and neuropathological changes during the preclinical stages (onset approximately 24–30 months of age) of canine MPS IIIB disease. Even by 1 month of age, MPS IIIB dogs had elevated HS levels in brain and cerebrospinal fluid. Analysis of histopathology of several disease-relevant regions of the forebrain demonstrated progressive lysosomal storage and microglial activation despite a lack of cerebrocortical atrophy in the oldest animals studied. More pronounced histopathology changes were detected in the cerebellum, where progressive lysosomal storage, astrocytosis and microglial activation were observed. Microglial activation was particularly prominent in cerebellar white matter and within the deep cerebellar nuclei, where neuron loss also occurred. The findings in this study will form the basis of future assessments of therapeutic efficacy in this large animal disease model.Martin T. EgelandMarta M. Tarczyluk-WellsMelissa M. AsmarEvan G. AdintoriRoger LawrenceElizabeth M. SnellaJackie K. JensBrett E. CrawfordJill C. M. WaitEmma McCullaghJason PinkstaffJonathan D. CooperN. Matthew EllinwoodNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-16 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Martin T. Egeland Marta M. Tarczyluk-Wells Melissa M. Asmar Evan G. Adintori Roger Lawrence Elizabeth M. Snella Jackie K. Jens Brett E. Crawford Jill C. M. Wait Emma McCullagh Jason Pinkstaff Jonathan D. Cooper N. Matthew Ellinwood Central nervous system pathology in preclinical MPS IIIB dogs reveals progressive changes in clinically relevant brain regions
description	Abstract Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B) is an autosomal recessive lysosomal storage disorder caused by the deficiency of alpha-N-acetylglucosaminidase activity, leading to increased levels of nondegraded heparan sulfate (HS). A mouse model has been useful to evaluate novel treatments for MPS IIIB, but has limitations. In this study, we evaluated the naturally occurring canine model of MPS IIIB for the onset and progression of biochemical and neuropathological changes during the preclinical stages (onset approximately 24–30 months of age) of canine MPS IIIB disease. Even by 1 month of age, MPS IIIB dogs had elevated HS levels in brain and cerebrospinal fluid. Analysis of histopathology of several disease-relevant regions of the forebrain demonstrated progressive lysosomal storage and microglial activation despite a lack of cerebrocortical atrophy in the oldest animals studied. More pronounced histopathology changes were detected in the cerebellum, where progressive lysosomal storage, astrocytosis and microglial activation were observed. Microglial activation was particularly prominent in cerebellar white matter and within the deep cerebellar nuclei, where neuron loss also occurred. The findings in this study will form the basis of future assessments of therapeutic efficacy in this large animal disease model.
format	article
author	Martin T. Egeland Marta M. Tarczyluk-Wells Melissa M. Asmar Evan G. Adintori Roger Lawrence Elizabeth M. Snella Jackie K. Jens Brett E. Crawford Jill C. M. Wait Emma McCullagh Jason Pinkstaff Jonathan D. Cooper N. Matthew Ellinwood
author_facet	Martin T. Egeland Marta M. Tarczyluk-Wells Melissa M. Asmar Evan G. Adintori Roger Lawrence Elizabeth M. Snella Jackie K. Jens Brett E. Crawford Jill C. M. Wait Emma McCullagh Jason Pinkstaff Jonathan D. Cooper N. Matthew Ellinwood
author_sort	Martin T. Egeland
title	Central nervous system pathology in preclinical MPS IIIB dogs reveals progressive changes in clinically relevant brain regions
title_short	Central nervous system pathology in preclinical MPS IIIB dogs reveals progressive changes in clinically relevant brain regions
title_full	Central nervous system pathology in preclinical MPS IIIB dogs reveals progressive changes in clinically relevant brain regions
title_fullStr	Central nervous system pathology in preclinical MPS IIIB dogs reveals progressive changes in clinically relevant brain regions
title_full_unstemmed	Central nervous system pathology in preclinical MPS IIIB dogs reveals progressive changes in clinically relevant brain regions
title_sort	central nervous system pathology in preclinical mps iiib dogs reveals progressive changes in clinically relevant brain regions
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/5500192f556445fb9991fe7f6927c244
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Central nervous system pathology in preclinical MPS IIIB dogs reveals progressive changes in clinically relevant brain regions

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