Neuronal pentraxin 1 depletion delays neurodegeneration and extends life in Sandhoff disease mice.

Abstract

GM2 gangliosidoses are a group of lysosomal storage disorders which include Sandhoff disease and Tay-Sachs disease. Dysregulation of glutamate receptors has been recently postulated in the pathology of Sandhoff disease. Glutamate receptor association with neuronal pentraxins 1 and 2, and the neuronal pentraxin receptor facilitates receptor potentiation and synaptic shaping. In this study, we have observed an upregulation of a novel form of neuronal pentraxin 1 (NP1-38) in the brains of a mouse model of Sandhoff disease and Tay-Sachs disease. In order to determine the impact of NP1 on the pathophysiology of Sandhoff disease mouse models, we have generated an Np1-/-Hexb-/- double knockout mouse, and observed extended lifespan, improved righting reflex and enhanced body condition relative to Hexb-/- mice, with no effect on gliosis or apoptotic markers in the CNS. Sandhoff mouse brain slices reveals a reduction in AMPA receptor-mediated currents, and increased variability in total glutamate currents in the CA1 region of the hippocampus; Np1-/-Hexb-/- mice show a correction of this phenotype, suggesting NP1-38 may be interfering with glutamate receptor function. Indeed, some of the psychiatric aspects of Sandhoff and Tay-Sachs disease (particularly late onset) may be attributed to a dysfunctional hippocampal glutamatergic system. Our work highlights a potential role for synaptic proteins, such as NP1 and glutamate receptors in lysosomal storage diseases.

• Authors: Alexander W M Hooper, Javier F Alamilla, Rosemarie E Venier, Deda C Gillespie, Suleiman A Igdoura
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 26 Issue 4 Pg. 661-673 (02 15 2017) ISSN: 1460-2083 [Electronic] England
• PMID: 28007910 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Nerve Tissue Proteins
• neuronal pentraxin
• C-Reactive Protein
• beta-Hexosaminidase beta Chain

Topics

• Animals
• C-Reactive Protein (biosynthesis, genetics)
• CA1 Region, Hippocampal (metabolism, pathology)
• Humans
• Mice
• Mice, Knockout
• Nerve Tissue Proteins (biosynthesis, genetics)
• Sandhoff Disease (metabolism, pathology)
• Up-Regulation
• beta-Hexosaminidase beta Chain (biosynthesis, genetics)