Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/131274
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Type: Journal article
Title: Comparative analysis of brain pathology in heparan sulphate storing mucopolysaccharidoses
Author: Derrick-Roberts, A.
Kaidonis, X.
Jackson, M.R.
Liaw, W.C.
Ding, X.D.
Ong, C.
Ranieri, E.
Sharp, P.
Fletcher, J.
Byers, S.
Citation: Molecular Genetics and Metabolism, 2020; 131(1-2):197-205
Publisher: Elsevier
Issue Date: 2020
ISSN: 1096-7192
1096-7206
Statement of
Responsibility: 
Ainslie Derrick-Roberts, Xenia Kaidonis, Matilda R.Jackson, Wan Chin Liaw, XiaoDan Ding, Chun Ong ... et al.
Abstract: The cause of neurodegeneration in MPS mouse models is the focus of much debate and what the underlying cause of disease pathology in MPS mice is. The timing of development of pathology and when this can be reversed or impacted is the key to developing suitable therapies in MPS. This study is the first of its kind to correlate the biochemical changes with the functional outcome as assessed using non-invasive behaviour testing across multiple mucopolysaccharidosis (MPS) mouse models. In the MPS brain, the primary lysosomal enzyme dysfunction leads to accumulation of primary glycosaminoglycans (GAGs) with gangliosides (GM2 and GM3) being the major secondary storage products. With a focus on the neuropathology, a time course experiment was conducted in MPS I, MPS IIIA, MPS VII (severe and attenuated models) in order to understand the relative timing and level of GAG and ganglioside accumulation and how this correlates to behaviour deficits. Time course analysis from 1 to 6 months of age was conducted on brain samples to assess primary GAG (uronic acid), β-hexosaminidase enzyme activity and levels of GM2 and GM3 gangliosides. This was compared to a battery of non-invasive behaviour tests including open field, inverted grid, rotarod and water cross maze were assessed to determine effects on motor function, activity and learning ability. The results show that the GAG and ganglioside accumulation begins prior to the onset of detectable changes in learning ability and behaviour. Interestingly, the highest levels of GAG and ganglioside accumulation was observed in the MPS IIIA mouse despite having 3% residual enzyme activity. Deficits in motor function were clearly observed in the severe Gusmps/mps, which were significantly delayed in the attenuated Gustm(L175F)Sly model despite their minimal increase in detectable enzyme activity. This suggests that genotype and residual enzyme activity are not indicative of severity of disease pathology in MPS disease and there exists a window when there are considerable storage products without detectable functional deficits which may allow an alteration to occur with therapy.
Keywords: Brain
Animals
Humans
Mice
Mucopolysaccharidosis I
Mucopolysaccharidosis III
Mucopolysaccharidosis VII
Disease Models, Animal
Glucuronidase
G(M2) Ganglioside
G(M3) Ganglioside
Glycosaminoglycans
Heparitin Sulfate
Maze Learning
Male
Rights: Crown Copyright © 2020 Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ymgme.2020.07.006
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