Neuraminidase 1 secondary deficiency contributes to CNS pathology in neurological mucopolysaccharidoses via brain protein hypersialylation
TianMeng Xu, Rachel Heon-Roberts, Travis Moore, Patricia Dubot, Xuefang Pan, Tianlin Guo, Christopher W. Cairo, Rebecca J. Holley, Brian Bigger, Thomas M. Durcan, Thierry Levade, Jerôme Ausseil, Bénédicte Amilhon, Alexei Gorelik, Bhushan Nagar, Shaukat Khan, Shunji Tomatsu, Luisa Sturiale, Angelo Palmigiano, Iris Röckle, Hauke Thiesler, Herbert Hildebrandt, Domenico Garozzo, Alexey V. Pshezhetsky
TianMeng Xu, Rachel Heon-Roberts, Travis Moore, Patricia Dubot, Xuefang Pan, Tianlin Guo, Christopher W. Cairo, Rebecca J. Holley, Brian Bigger, Thomas M. Durcan, Thierry Levade, Jerôme Ausseil, Bénédicte Amilhon, Alexei Gorelik, Bhushan Nagar, Shaukat Khan, Shunji Tomatsu, Luisa Sturiale, Angelo Palmigiano, Iris Röckle, Hauke Thiesler, Herbert Hildebrandt, Domenico Garozzo, Alexey V. Pshezhetsky
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Research Article Genetics Neuroscience

Neuraminidase 1 secondary deficiency contributes to CNS pathology in neurological mucopolysaccharidoses via brain protein hypersialylation

Abstract

Mucopolysaccharidoses (MPS) are lysosomal storage diseases caused by defects in catabolism of glycosaminoglycans. MPS I, II, III, and VII, which are associated with lysosomal accumulation of heparan sulphate (HS), manifest with neurological deterioration and currently lack effective treatments. We report that neuraminidase 1 (NEU1) activity is drastically reduced in brain tissues of patients with neurological MPS and mouse models but not in neurological lysosomal disorders without HS storage. Accumulated HS disrupts the lysosomal multienzyme complex of NEU1 with cathepsin A, β-galactosidase (GLB1), and glucosamine-6-sulfate sulfatase (GALNS), leading to NEU1 deficiency and partial GLB1 and GALNS deficiencies in cortical tissues and induced pluripotent stem cell–derived (iPSC-derived) cortical neurons of patients with neurological MPS. Increased sialylation of N-linked glycans in brains of patients with MPS and mice implicated insufficient processing of sialylated glycans, except for polysialic acid. Correction of NEU1 activity in MPS IIIC mice by lentiviral (LV) gene transfer ameliorated previously identified hallmarks of the disease, including memory impairment, behavioral traits, and reduced levels of excitatory synapse markers VGLUT1 and PSD95. Overexpression of NEU1 also restored levels of VGLUT1/PSD95–positive puncta in cortical iPSC-derived MPS IIIA neurons. Our results demonstrate that HS-induced secondary NEU1 deficiency and aberrant sialylation of brain glycoproteins constitute what we believe is a novel pathological pathway in the neurological MPS spectrum crucially contributing to CNS pathology.

Authors

TianMeng Xu, Rachel Heon-Roberts, Travis Moore, Patricia Dubot, Xuefang Pan, Tianlin Guo, Christopher W. Cairo, Rebecca J. Holley, Brian Bigger, Thomas M. Durcan, Thierry Levade, Jerôme Ausseil, Bénédicte Amilhon, Alexei Gorelik, Bhushan Nagar, Shaukat Khan, Shunji Tomatsu, Luisa Sturiale, Angelo Palmigiano, Iris Röckle, Hauke Thiesler, Herbert Hildebrandt, Domenico Garozzo, Alexey V. Pshezhetsky

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Figure 9

HgsnatP304L mice treated with LV-CTSA-IRES-NEU1-GFP show a partial rescue of behavior abnormalities.

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HgsnatP304L mice treated with LV-CTSA-IRES-NEU1-GFP show a partial resc...
(A) Improvement of the short-term memory in HgsnatP304L mice injected with LV-CTSA-IRES-NEU1-GFP. Discrimination index and the percentage of time spent exploring the novel object were measured using the NOR test in 6-month-old WT mice, WT mice injected with LV-CTSA-IRES-NEU1-GFP, HgsnatP304L mice, and HgsnatP304L mice injected with LV-CTSA-IRES-NEU1-GFP or LV-GFP. HgsnatP304L mice injected with LV-CTSA-IRES-NEU1-GFP had a higher discrimination index and more time spent with the new object than did control or sham-treated HgsnatP304L mice. (B) HgsnatP304L mice injected with LV-CTSA-IRES-NEU1-GFP show normalization of anxiety as revealed by the OF test. Graphs show the percentage of time spent in the center of the arena, the percentage of the distance traveled in the center zone, and the number of entries to the center of the arena. All graphs show individual data and means ± SD (n = 6–11). **P < 0.01, ***P < 0.001, ****P < 0.0001, determined by 1-way ANOVA with a Tukey’s post hoc test.