Pro-apoptotic function of GABA-related transcripts following stroke.
Nadine Jaenisch1, Anke Popp1, Madlen Guenther1
1Hans Berger Department of Neurology, Jena University Hospital, Friedrich Schiller University, Erlanger Allee 101, 07747 Jena, Germany.
Neurobiology of Disease
|July 2, 2014
Summary
Embryonic splice variants of the GAD67 gene (EGAD) are re-expressed in adult brain neurons after stroke, promoting cell death. Blocking EGAD reduced apoptosis, suggesting a novel therapeutic target for stroke recovery.
Area of Science:
- Neuroscience
- Molecular Biology
- Developmental Biology
Background:
- Cerebral injuries like stroke trigger tissue reorganization and re-expression of developmental genes.
- Embryonic splice variants of GAD67 (EGAD) are crucial for neuronal development, including proliferation, migration, and differentiation.
Purpose of the Study:
- To investigate the hypothesized involvement of EGAD in post-ischemic plasticity and neuronal cell death.
- To explore the role of EGAD in the adult brain under pathophysiological conditions.
Main Methods:
- Transient middle cerebral artery occlusion in mice to induce stroke.
- Radioactive in situ hybridization and immunolabeling for cell-specific analysis.
- In vitro models of ischemia (oxygen-glucose deprivation) and apoptosis (staurosporine treatment).
- Antisense RNA treatment to block EGAD expression.
Main Results:
- EGAD transcripts were significantly upregulated in the injured brain area post-stroke, peaking at 6 hours.
- EGAD was notably upregulated in TUNEL-positive neurons, indicating an association with cell death.
- EGAD re-expression was confirmed in cell culture models of ischemia and apoptosis.
- Blocking EGAD expression reduced staurosporine-induced cleaved Caspase-3 activation by approximately 30%.
Conclusions:
- EGAD plays a role in cell death under pathophysiological conditions in the adult brain, distinct from its developmental functions.
- Re-expressed EGAD in neurons post-stroke may contribute to aberrant cell cycle activation and apoptosis.
- This study identifies a novel GABA-related pro-apoptotic mechanism with potential clinical relevance for stroke treatment.
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