- Library Home /
- Search Collections /
- Open Collections /
- Browse Collections /
- UBC Theses and Dissertations /
- Neuroprotection by peptides designed to block interactions...
Open Collections
UBC Theses and Dissertations
UBC Theses and Dissertations
Neuroprotection by peptides designed to block interactions between glutamate receptors and neuronal activity regulated pentraxin Smith, Carlo
Abstract
Excitotoxicity is caused by prolonged stimulation of N-methyl-D-aspartate type glutamate receptors (NMDARs) resulting in internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type glutamate receptors (AMPARs) and long-term depression (LTD) of post-synaptic response, and this process has been causally linked to neuronal cell death. Indeed, NMDAR/AMPAR excitotoxicity is believed to underlie neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease and ischaemic brain injury. Neuronal activity regulated pentraxin (NARP) is a secreted immediate early gene product that binds to and clusters AMPAR subunits GluR1-4 in response to normal and pathological synaptic activity. To test whether NARP could potentiate excitotoxic neuronal death by clustering AMPARs at cortical synapses, we used peptide arrays to develop four peptides that mimic sites on GluR1 that might bind NARP. Three of the four peptides correspond to sites on the N-terminal domain of GluR1, a region previously implicated in facilitating NARP-mediated GluR1 clustering at synapses. We show that NARP is up-regulated 4-8 hours after excitotoxic NMDA treatment of primary cortical neurons. We found that a mixture of all four peptides inhibited NMDA-induced GluR1 internalization and was neuroprotective in a dose-dependent manner. Also, three of peptides were individually neuroprotective. We conclude that the peptides inhibit NARP’s ability to form synaptic GluR1 clusters which may be required for coordinated and sustained GluR1 internalization 4-8 hours after NMDA stimulation. This is an essential step in NMDA-induced cell death since blocking it is neuroprotective. These peptides suggest new approaches to treatment of neurodegenerative diseases caused by excitotoxicity.
Item Metadata
Title |
Neuroprotection by peptides designed to block interactions between glutamate receptors and neuronal activity regulated pentraxin
|
Creator | |
Publisher |
University of British Columbia
|
Date Issued |
2012
|
Description |
Excitotoxicity is caused by prolonged stimulation of N-methyl-D-aspartate type glutamate receptors (NMDARs) resulting in internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type glutamate receptors (AMPARs) and long-term depression (LTD) of post-synaptic response, and this process has been causally linked to neuronal cell death. Indeed, NMDAR/AMPAR excitotoxicity is believed to underlie neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease and ischaemic brain injury. Neuronal activity regulated pentraxin (NARP) is a secreted immediate early gene product that binds to and clusters AMPAR subunits GluR1-4 in response to normal and pathological synaptic activity. To test whether NARP could potentiate excitotoxic neuronal death by clustering AMPARs at cortical synapses, we used peptide arrays to develop four peptides that mimic sites on GluR1 that might bind NARP. Three of the four peptides correspond to sites on the N-terminal domain of GluR1, a region previously implicated in facilitating NARP-mediated GluR1 clustering at synapses. We show that NARP is up-regulated 4-8 hours after excitotoxic NMDA treatment of primary cortical neurons. We found that a mixture of all four peptides inhibited NMDA-induced GluR1 internalization and was neuroprotective in a dose-dependent manner. Also, three of peptides were individually neuroprotective. We conclude that the peptides inhibit NARP’s ability to form synaptic GluR1 clusters which may be required for coordinated and sustained GluR1 internalization 4-8 hours after NMDA stimulation. This is an essential step in NMDA-induced cell death since blocking it is neuroprotective. These peptides suggest new approaches to treatment of neurodegenerative diseases caused by excitotoxicity.
|
Genre | |
Type | |
Language |
eng
|
Date Available |
2012-09-05
|
Provider |
Vancouver : University of British Columbia Library
|
Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
|
DOI |
10.14288/1.0073128
|
URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
|
Graduation Date |
2012-11
|
Campus | |
Scholarly Level |
Graduate
|
Rights URI | |
Aggregated Source Repository |
DSpace
|
Item Media
Item Citations and Data
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International