Format

Send to

Choose Destination
FASEB J. 2017 Aug;31(8):3467-3483. doi: 10.1096/fj.201601299R. Epub 2017 Apr 25.

Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides.

Author information

1
Sainte-Justine University Hospital Research Center, University of Montreal, Montreal, Quebec, Canada.
2
Department of Anatomy and Cell Biology, Research Institute of the McGill University Health Center, McGill University, Montreal, Quebec, Canada.
3
Universidad Autónoma de Madrid, Madrid, Spain.
4
Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
5
Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, Sendai, Japan.
6
Miyagi Cancer Center Research Institute, Natori, Japan.
7
Consiglio Nazionale delle Ricerche, Institute for Polymers, Composites, and Biomaterials, Catania, Italy.
8
Sainte-Justine University Hospital Research Center, University of Montreal, Montreal, Quebec, Canada; alexei.pchejetski@umontreal.ca.

Abstract

Gangliosides (sialylated glycolipids) play an essential role in the CNS by regulating recognition and signaling in neurons. Metabolic blocks in processing and catabolism of gangliosides result in the development of severe neurologic disorders, including gangliosidoses manifesting with neurodegeneration and neuroinflammation. We demonstrate that 2 mammalian enzymes, neuraminidases 3 and 4, play important roles in catabolic processing of brain gangliosides by cleaving terminal sialic acid residues in their glycan chains. In neuraminidase 3 and 4 double-knockout mice, GM3 ganglioside is stored in microglia, vascular pericytes, and neurons, causing micro- and astrogliosis, neuroinflammation, accumulation of lipofuscin bodies, and memory loss, whereas their cortical and hippocampal neurons have lower rate of neuritogenesis in vitro Double-knockout mice also have reduced levels of GM1 ganglioside and myelin in neuronal axons. Furthermore, neuraminidase 3 deficiency drastically increased storage of GM2 in the brain tissues of an asymptomatic mouse model of Tay-Sachs disease, a severe human gangliosidosis, indicating that this enzyme is responsible for the metabolic bypass of β-hexosaminidase A deficiency. Together, our results provide the first in vivo evidence that neuraminidases 3 and 4 have important roles in CNS function by catabolizing gangliosides and preventing their storage in lipofuscin bodies.-Pan, X., De Britto Pará De Aragão, C., Velasco-Martin, J. P., Priestman, D. A., Wu, H. Y., Takahashi, K., Yamaguchi, K., Sturiale, L., Garozzo, D., Platt, F. M., Lamarche-Vane, N., Morales, C. R., Miyagi, T., Pshezhetsky, A. V. Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides.

KEYWORDS:

Tay-Sach disease; gangliosidosis; lipofuscin; lysosomal storage; neuroinflammation; sialidase

PMID:
28442549
DOI:
10.1096/fj.201601299R
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center