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Comparative analysis of brain pathology in heparan sulphate storing mucopolysaccharidoses.

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.

journal_name

Mol Genet Metab

journal_title

Molecular genetics and metabolism

authors

Derrick-Roberts A,Kaidonis X,Jackson MR,Liaw WC,Ding X,Ong C,Ranieri E,Sharp P,Fletcher J,Byers S

doi

10.1016/j.ymgme.2020.07.006

subject

Has Abstract

pub_date

2020-01-01 00:00:00

pages

197-205

issue

1-2

eissn

1096-7192

issn

1096-7206

pii

S1096-7192(20)30175-X

journal_volume

131

pub_type

杂志文章

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Comparative analysis of brain pathology in heparan sulphate storing mucopolysaccharidoses.