Ischemic stroke is the third leading cause of death in developed countries. A critical feature of the disease is a highly selective pattern of neuronal loss; certain identifiable subsets of neurons, particularly CA1 pyramidal neurons in the hippocampus, are severely damaged while others remain intact. A step in this selective neuronal injury involves Ca2+ entry through Ca2+-permeable AMPA receptor channels. AMPA receptors are a major subtype of glutamate receptors (GluRs) that are assembled from GluR1-4 subunits. Ca2+ permeability of the channels is dominated by GluR2 RNA editing at the Q/R site; edited GluR2(R) subunits form Ca2+-impermeable channels, whereas unedited GluR2(Q) channels allow Ca2+ entry. In most CA1 neurons, AMPA receptor channels contain GluR2(R), and thus are impermeable to Ca2+ flow. Recently, we have identified that transient forebrain ischemia selectively disrupts GluR2 Q/R site editing and hence induces injurious Ca2+ entry through AMPA receptor channels into vulnerable CA1 neurons. We have also shown that impaired GluR2 Q/R site editing is closely correlated with reduced expression of ADAR2 (short for adenosine deaminase acting on RNA) gene, a nuclear enzyme responsible for GluR2 Q/R site editing. We thus hypothesize that reduced expression of ADAR2 gene is responsible for the impaired GluR2 Q/R site editing. To address this hypothesis directly, we will determine if restoration of ADAR2 gene expression rescues GluR2 Q/R site editing and in turn blocks Ca2+ permeability of AMPA receptor channels, leading to the survival of vulnerable neurons in the post-ischemic rats. Overall, this project will have two specific aims:
Specific Aim 1 : To determine whether restoration of ADAR2 gene expression blocks Ca2+ entry through AMPA receptor channels and rescues vulnerable neurons in the post-ischemic rats.
Specific Aim 2 : To determine if generation of stable ADAR2 gene silencing induces degeneration of ischemia-insensitive neurons, and if degeneration of ADAR2-deficient neurons results from RNA editing deficits of one or more glutamate receptor subunits. Together, this project will identify that ADAR2-dependent GluR2 Q/R site editing determines vulnerability of neurons to ischemia. Thus, this work will define a promising target for stoke therapy.
| Yang, Ying; Shu, Xiaogang; Liu, Dan et al. (2012) EPAC null mutation impairs learning and social interactions via aberrant regulation of miR-124 and Zif268 translation. Neuron 73:774-88 |
| Tu, Weihong; Xu, Xin; Peng, Lisheng et al. (2010) DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. Cell 140:222-34 |
| Kim, Dohoon; Frank, Christopher L; Dobbin, Matthew M et al. (2008) Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron 60:803-17 |
| Qiao, Liyan; Hamamichi, Shusei; Caldwell, Kim et al. (2008) Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity. Mol Brain 1:17 |
