DEATH-ASSOCIATED PROTEIN Kinase1 (DAPK 1) INTERACTS WITH EXTRA-SYNAPTIC NMethyl-D-Aspartic Acid (NMDA) RECEPTORS IN HUNTINGTON'S DISEASE
Document Type
Presentation
Start Date
22-10-2010 10:45 AM
End Date
22-10-2010 12:00 PM
Description
Huntington disease (HD) is an inherited neurodegenerative disorder that is caused by an expansion of a poly-glutamine repeat in the amino terminal of huntingtin (htt). A critical feature of the disease is a highly selective pattern of neuronal loss; certain identifiable subsets of neurons are degenerated, including medium spiny neurons (MSNs) in the striatum, and pyramidal neurons in the cortex, whereas other neurons in the brain remain intact. One step in this selective neuronal loss involves excessive stimulation of NMDA receptor channels.
We have recently demonstrated that DAPK1 acts as a specific extra-synaptic NMDA receptor cell death signaling in the brain. The earlier studies revealed an excessive activation of extra-synaptic NMDA receptors in HD mice. I thus hypothesize that DAPK1 may function as an essential mediator that links extra-synaptic NMDA receptor activation to the progression of neuronal pathological changes in HD. To test this possibility, I measured the catalytic activity of DAPK1 in the striatum of R6/2 mice, a well-established mouse model with HD, using immunecomplex kinase assay with myosin light chain (MLC) as an endogenous substrate. In this study, the R6/2 mice expressing the human HD gene with the 160 ± 10 CAG repeats (R6/2 mice). Similar to human disease, R6/2 mice show the progressive neuronal pathological phenotypes with cognitive and motor deficits. With the aim of developing strategies to intervene onset and progression of HD, I focused my efforts on DAPK1 activation in the pre-symptomatic R6/2 mice. I found that catalytic activity of DAPK1 began to increase in 4 weeks old of R6/2 mice, and peaked at 6-weeks old of age (2.7 fold higher than controls). The elevated DAPK1 activity in R6/2 mice remained at 8 weeks old of age. The increased activity of DAPK1 was detected in the striatum but not in the hippocampus. Furthermore, I found that knock down of DAPK1 gene expression significantly attenuates the neuronal cell death in the striatum of HD mice. Thus, DAPK1 mediates extra-synaptic NMDA receptor activation in the progression of neuronal pathological changes in HD.
Recommended Citation
Qian, Kun and Lu, Youming, "DEATH-ASSOCIATED PROTEIN Kinase1 (DAPK 1) INTERACTS WITH EXTRA-SYNAPTIC NMethyl-D-Aspartic Acid (NMDA) RECEPTORS IN HUNTINGTON'S DISEASE" (2010). Dr. Joseph M. Moerschbaecher, III Graduate Research Day. 18.
https://digitalscholar.lsuhsc.edu/grad_rs/2010/poster1/18
DEATH-ASSOCIATED PROTEIN Kinase1 (DAPK 1) INTERACTS WITH EXTRA-SYNAPTIC NMethyl-D-Aspartic Acid (NMDA) RECEPTORS IN HUNTINGTON'S DISEASE
Huntington disease (HD) is an inherited neurodegenerative disorder that is caused by an expansion of a poly-glutamine repeat in the amino terminal of huntingtin (htt). A critical feature of the disease is a highly selective pattern of neuronal loss; certain identifiable subsets of neurons are degenerated, including medium spiny neurons (MSNs) in the striatum, and pyramidal neurons in the cortex, whereas other neurons in the brain remain intact. One step in this selective neuronal loss involves excessive stimulation of NMDA receptor channels.
We have recently demonstrated that DAPK1 acts as a specific extra-synaptic NMDA receptor cell death signaling in the brain. The earlier studies revealed an excessive activation of extra-synaptic NMDA receptors in HD mice. I thus hypothesize that DAPK1 may function as an essential mediator that links extra-synaptic NMDA receptor activation to the progression of neuronal pathological changes in HD. To test this possibility, I measured the catalytic activity of DAPK1 in the striatum of R6/2 mice, a well-established mouse model with HD, using immunecomplex kinase assay with myosin light chain (MLC) as an endogenous substrate. In this study, the R6/2 mice expressing the human HD gene with the 160 ± 10 CAG repeats (R6/2 mice). Similar to human disease, R6/2 mice show the progressive neuronal pathological phenotypes with cognitive and motor deficits. With the aim of developing strategies to intervene onset and progression of HD, I focused my efforts on DAPK1 activation in the pre-symptomatic R6/2 mice. I found that catalytic activity of DAPK1 began to increase in 4 weeks old of R6/2 mice, and peaked at 6-weeks old of age (2.7 fold higher than controls). The elevated DAPK1 activity in R6/2 mice remained at 8 weeks old of age. The increased activity of DAPK1 was detected in the striatum but not in the hippocampus. Furthermore, I found that knock down of DAPK1 gene expression significantly attenuates the neuronal cell death in the striatum of HD mice. Thus, DAPK1 mediates extra-synaptic NMDA receptor activation in the progression of neuronal pathological changes in HD.