Molecular mechanism of lysosomal sialidase deficiency in galactosialidosis involves its rapid degradation
Open accessAbstract
Galactosialidosis is an inherited lysosomal storage disease caused by the combined deficiency of lysosomal sialidase and β-galactosidase secondary to the deficiency of cathepsin A/protective protein, which is associated with sialidase and β-galactosidase in a high-molecular weight (1.27 MDa) complex. Clinical phenotypes of patients as well as the composition of compounds which are stored in patient's tissues implicate sialidase deficiency as the underlying pathogenic defect. The recent cloning and sequencing of lysosomal sialidase [Pshezhetsky, Richard, Michaud, Igdoura, Wang, Elsliger, Qu, Leclerc, Gravel, Dallaire and Potier (1997), Nature Genet. 15, 316-320] allowed us to study the molecular mechanism of sialidase deficiency in galactosialidosis. By Western blotting, using antibodies against the recombinant human enzyme, and by NH2-terminal sequencing, we showed that sialidase is synthesized as a 45.5 kDa precursor and after the cleavage of the 47-amino acid signal peptide and glycosylation becomes a 48.3 kDa mature active enzyme present in the 1.27 kDa complex. Transgenic expression of sialidase in cultured skin fibroblasts from normal controls and from galactosialidosis patients, followed by immunofluorescent and immunoelectron microscopy showed that in both normal and affected cells the expressed sialidase was localized on lysosomal and plasma membranes, but the amount of sialidase found in galactosialidosis cells was ~ 5-fold reduced. Metabolic labelling studies demonstrated that the 48.3 kDa mature active form of sialidase was stable in normal fibroblasts (half-life ~ 2.7 h), whereas in galactosialidosis fibroblasts the enzyme was rapidly converted (half-life ~ 30 min) into 38.7 and 24 kDa catalytically inactive forms. Altogether our data provide evidence that the molecular mechanism of sialidase deficiency in galactosialidosis is associated with abnormal proteolytic cleavage and fast degradation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
CTSA protects NEU1 from proteolytic degradation.
“It facilitates the transport of NEU1 to lysosomes (33), protects it from proteolytic degradation (30), and was suggested to induce a conformational change in NEU1, enabling its enzymatic activity (12, 22, 30, 33).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [30]
NEU1 is not activated via proteolysis.
“Although CTSA also functions as a protease, NEU1 is not activated via proteolysis (23, 24, 30, 80).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [30]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
No references could be resolved yet.
Research works printed but not linked: 6
- 1 d'Azzo, A., Hoogeveen, A., Reuser, A. J., Robinson, D. and Galjaard, H. (1982) Proc. Natl. Acad. Sci. U.S.A. 79 , 4535-4539
- 6 d'Azzo, A., Andria, G., Strisciuglio, P. and Galijaard, H. (1995) in Metabolic and Molecular Bases of Inherited Disease (Scriver, C. R., Beaudet, A. L., Sly, W. S. and Valle, D., eds.), pp. 2835-2837, McGraw-Hill, New York
- 8 Thomas, G. H. and Beaudet, A. L. (1995) in The Metabolic and Molecular Bases of Inherited Disease (Scriber, C. R., Beaudt, A. L., Sly, W. S. and Valle, D., eds.), pp. 2542-2545, McGraw-Hill, New York
- 10 Shimmoto, M., Takano, T., Fukuhara, Y., Oshima, A., Sakuraba, H. and Suzuki, Y. (1990) Proc. Jpn. Acad. 66B , 217-222
- 25 Thiobarbituric assay for sialic acids with spectrophotometric or HPLC detection, in Current Protocols in Molecular Biology, ed. Ford, N. (Cold Spring Harbor Lab. Press, 1989), Supp. 3
- 42 Van der Horst, G. T. J. (1993) Ph.D. Thesis (Erasmus University Press, Amsterdam)
Cited by
Sorted by citations
Structure of the immunoregulatory sialidase NEU1
Gorelik, A., Illes, K., Mazhab-Jafari, M. T., & Nagar, B. (2023) · Science Advances · doi:10.1126/sciadv.adf8169 · Cited by 36 · see citing works
- Authors
- VINOGRADOVA, V. M., MICHAUD, L., MEZENTSEV, V. A., LUKONG, E. K., EL-ALFY, M., MORALES, R. C., POTIER, M., & PSHEZHETSKY, V. A.
- Affiliations
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Université de Montréal, Service de Génétique Médicale, Département de Pédiatrie, Hôpital Sainte-Justine, Montréal, Québec, H3T 1C5 Canada
- Department of Anatomy and Cell Biology, McGill University, Montréal, Québec, Canada
- McGill University (CA)
- Corresponding author
- MICHAUD, Lorraine
- POTIER, Michel
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 1998-03-01
- Volume
- 330
- Issue
- 2
- Pages
- 641-650
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1219185
- OpenAlex
- W2135574550
- Cited by
- 63
- References
- 0
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 3 · 2014: 2 · 2013: 5 · 2012: 4
- FWCI
- 2.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- galactosialidosis, enzyme degradation, proteolytic cleavage, cathepsin A, beta-galactosidase, lysosomal storage disease, transgene expression, dermal fibroblasts, enzyme half-life, glycosylation, signal peptide
- MeSH terms
- Animals, Cells, Cultured, Chromatography, High Pressure Liquid, Fibroblasts, Humans, Lysosomes, Molecular Weight, Neuraminidase, Rabbits, Microscopy, Immunoelectron, Lysosomal Storage Diseases, DNA, Complementary
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
