Neuraminidase 1 secondary deficiency contributes to CNS pathology in neurological mucopolysaccharidoses via brain protein hypersialylation
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
- Iris Röckle (ORCID: https://orcid.org/0000-0003-2621-2223)
- Thomas M. Durcan (ORCID: https://orcid.org/0000-0003-3942-1956)
- Jérôme Ausseil (ORCID: https://orcid.org/0000-0002-3059-9777)
- Bénédicte Amilhon (ORCID: https://orcid.org/0000-0003-3964-6661)
- Tianlin Guo (ORCID: https://orcid.org/0000-0001-5096-2070)
- Domenico Garozzo (ORCID: https://orcid.org/0000-0002-9087-9818)
- Hauke Thiesler (ORCID: https://orcid.org/0000-0001-5561-3988)
- Alexey V. Pshezhetsky (ORCID: https://orcid.org/0000-0002-6612-1062)
- Xuefang Pan (ORCID: https://orcid.org/0000-0002-4445-3787)
- Rachel Heon‐Roberts (ORCID: https://orcid.org/0000-0001-9723-2227)
- Herbert Hildebrandt (ORCID: https://orcid.org/0000-0002-1044-0881)
- Christopher W. Cairo (ORCID: https://orcid.org/0000-0003-3363-8708)
- Brian Bigger (ORCID: https://orcid.org/0000-0002-9708-1112)
- Patricia Dubot (ORCID: https://orcid.org/0000-0002-9493-5338)
- Rebecca Holley
- Luisa Sturiale (ORCID: https://orcid.org/0000-0002-3996-1138)
- Shaukat Khan (ORCID: https://orcid.org/0000-0001-7689-1258)
- Thierry Levade (ORCID: https://orcid.org/0000-0003-3793-2584)
- Shunji Tomatsu (ORCID: https://orcid.org/0000-0002-0673-2160)
- Travis I. Moore (ORCID: https://orcid.org/0000-0002-8503-6023)
- Bhushan Nagar (ORCID: https://orcid.org/0000-0001-9869-2110)
- A. Gorelik (ORCID: https://orcid.org/0000-0001-6236-4633)
- Angelo Palmigiano (ORCID: https://orcid.org/0000-0002-6130-1830)
- TianMeng Xu (ORCID: https://orcid.org/0000-0001-6862-4715)
Institutions
- Montreal Neurological Institute and Hospital (CA)
- Centre National de la Recherche Scientifique (FR)
- Alfred I. duPont Hospital for Children (US)
- University of Alberta (CA)
- Inserm (FR)
- Université Fédérale de Toulouse Midi-Pyrénées (FR)
- Manchester Academic Health Science Centre (GB)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- University of Manchester (GB)
- Medizinische Hochschule Hannover (DE)
- Centre de Recherches en Cancérologie de Toulouse (FR)
- Toulouse Mathematics Institute (FR)
- Institut de Pharmacologie et de Biologie Structurale (FR)
- MRC Centre for Regenerative Medicine (GB)
- Institute of Polymers, Composites and Biomaterials (IT)
- McGill University (CA)
- Université de Montréal (CA)
- University of Edinburgh (GB)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-06-17
- DOI
- https://doi.org/10.1172/jci177430
- Citations
- 3
- Primary Topic
- Lysosomal Storage Disorders Research
- Type
- article
- Field-Weighted Citation Impact
- 3.49
Funders
- Sanfilippo Children's Foundation
- Canadian Institutes of Health Research
- Canadian Glycomics Network