title: 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.affiliation: Department of Biology.
authors.forename: Alexander W M
authors.initials: AWM
authors.lastname: Hooper
authors.affiliation: Department of Psychology, Neuroscience & Behaviour and.
authors.forename: Javier F
authors.initials: JF
authors.lastname: Alamilla
authors.affiliation: Department of Biology.
authors.forename: Rosemarie E
authors.initials: RE
authors.lastname: Venier
authors.affiliation: Department of Psychology, Neuroscience & Behaviour and.
authors.forename: Deda C
authors.initials: DC
authors.lastname: Gillespie
authors.affiliation: Department of Biology.|Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
authors.forename: Suleiman A
authors.initials: SA
authors.lastname: Igdoura
mesh_terms: D000818:Animals; D002097:C-Reactive Protein / Q000096:biosynthesis* / Q000235:genetics; D056547:CA1 Region, Hippocampal / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D012497:Sandhoff Disease / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D054821:beta-Hexosaminidase beta Chain / Q000096:biosynthesis* / Q000235:genetics; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D009419:Nerve Tissue Proteins; D054821:beta-Hexosaminidase beta Chain; D000099153:Pentraxins