Upregulation of Neuronal Pentraxin 1 is Deterimental to the Excitatory Pathways and Survival of Sandhoff Mice
1. Department of Biology, McMaster University, Hamilton, Ont., Canada L8S 4L8; 2. Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, Ont., Canada L8S 4L8; 3. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ont., Canada L8S 4L8
Dysregulation of glutamate receptors has been implicated in neurodegenerative disorders, and recent evidence- including alterations in cerebellar glutamate receptor levels in Sandhoff disease mouse models (Hexb-/-) - suggests this may be the case in Sandhoff disease. Neuronal pentraxin 1 (NP1), which is involved in synaptic shaping, is highly upregulated in Hexb-/- mice and therefore is postulated to play a role in the progression of the disease. We have generated an Np1-/-Hexb-/- double knockout which has improved body condition, improved righting reflex performance and increased lifespan in comparison with Hexb-/- mice. In addition, we observed a reduction in AMPA-induced currents and increased variation in total currents in the CA1 region of the hippocampus of Hexb-/- mice, which is reversed in the absence of NP1. We have also observed an upregulation of a novel isoform of NP1 (NP1B) in Hexb-/- mice, and present evidence it is generated from an alternative transcript, through deletion of the normal start codon. Splicing does not appear to occur through the canonical splicing consensus sequence. Our results indicate that, while the extracellular NP1 may induce clustering and deregulation of the glutamate receptors, the unique smaller isoforms (NP1B) may be retained in the cytosol resulting in potentiation of the apoptotic pathway in Hexb-/- neurons. Discovery of a treatable pathway, separate from the known inflammatory pathways could lead to new avenues of medical interventions for sufferers of Sandhoff disease and other neurodegenerative diseases.