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Reelin Signaling Pathway and Mesial Temporal Lobe Epilepsy: A Causative Link
Tulika Gupta1, Mandeep Kaur1, Navneet Singla2
1Department of Anatomy, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
Introduction:
Mesial temporal lobe epilepsy (MTLE) is the most frequent form of partial epilepsy. Granule cell dispersion, resulting from aberrant neuronal migration in the hippocampus, is pathognomonic of MTLE. Reelin, a secreted neurodevelopmental glycoprotein has a crucial role in controlling the radial migration of neurons. Several animal studies have implicated Reelin in the MTLE pathogenesis Mesial temporal lobe epilepsy (MTLE) is the most frequent form of partial epilepsy. Granule cell dispersion, resulting from aberrant neuronal migration in the hippocampus, is pathognomonic of MTLE. Reelin, a secreted neurodevelopmental glycoprotein has a crucial role in controlling the radial migration of neurons. Several animal studies have implicated Reelin in the MTLE pathogenesis.
Methods:
The aim of this study was to investigate the Reelin signalling pathway in the MTLE patients. Therefore, we studied each step in the Reelin signalling pathway for the gene and protein expressions, in the hippocampal tissue obtained from patients undergoing surgery for MTLE and compared it with age matched normal autopsy cases.
Results:
We found statistically significant decrease (P<0.001) in the Reelin mRNA expression in MTLE patients. Among the two reelin receptors, apolipoprotein E receptor 2 (ApoER2) was significantly increased whereas very low density lipoprotein receptor (VLDLR) was decreased among the patients. Disabled 1 (Dab1), the downstream target of reelin, was found to be decreased. Dab1 in turn inhibits Cofilin, which is responsible for cytoskeletal reorganization, thus limiting aberrant neuronal migration. Statistically significant over expression of Cofilin protein was found in the patient group. Matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteases-1 (TIMP-1), both of which are involved in processing of Reelin, were down regulated in 70-85% of cases.
Conclusion:
The whole pathway was found to be deranged in MTLE. These results indicate that Reelin signalling pathway is disturbed at various points in the MTLE patients and might be involved in the pathogenesis & progression of MTLE. Our results extend the existing information regarding the components of the Reelin pathway and further, establish a link between pathway disturbance and MTLE.
Insights
Reelin signaling is disrupted in mesial temporal lobe epilepsy (MTLE) patients, with decreased Reelin mRNA and altered receptor expression, suggesting a role in MTLE pathogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Epilepsy Research
Background:
- Mesial temporal lobe epilepsy (MTLE) is the most common partial epilepsy.
- Granule cell dispersion in the hippocampus is a hallmark of MTLE, linked to aberrant neuronal migration.
- Reelin, a glycoprotein, is vital for neuronal migration, and animal studies suggest its involvement in MTLE.
Purpose of the Study:
- To investigate the Reelin signaling pathway in human MTLE patients.
- To analyze gene and protein expressions of Reelin pathway components in hippocampal tissue from MTLE patients and controls.
Main Methods:
- Hippocampal tissue from MTLE patients and age-matched autopsy controls was analyzed.
- Gene (mRNA) and protein expressions of Reelin, its receptors (ApoER2, VLDLR), downstream targets (Dab1, Cofilin), and processing enzymes (MMP-9, TIMP-1) were assessed.
Main Results:
- Reelin mRNA expression was significantly decreased in MTLE patients.
- ApoER2 receptor expression was increased, while VLDLR expression decreased.
- Downstream signaling showed decreased Dab1 and increased Cofilin, with down-regulation of MMP-9 and TIMP-1.
Conclusions:
- The Reelin signaling pathway is significantly disturbed in MTLE.
- Aberrant Reelin pathway components may contribute to the pathogenesis and progression of MTLE.
- This study establishes a link between Reelin pathway disruption and MTLE in human patients.
