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Platelet-activating factor (PAF) acetylhydrolase activity, LIS1 expression, and seizures
O Shmueli1, A Cahana, O Reiner
1Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.
Insights
Reduced LIS1 gene expression and platelet-activating factor acetylhydrolase (PAF-AH) activity are linked to seizures in lissencephaly. This study reveals a correlation between LIS1 and PAF-AH activity, offering insights into seizure susceptibility.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Lissencephaly is a severe brain malformation characterized by recurrent seizures.
- The LIS1 gene, implicated in lissencephaly, encodes a subunit of platelet-activating factor acetylhydrolase (PAF-AH) and influences microtubule dynamics.
- The molecular mechanisms linking LIS1 dysfunction to seizures require further elucidation.
Purpose of the Study:
- To investigate the molecular involvement of LIS1 in seizure pathogenesis.
- To establish a correlation between LIS1 expression, PAF-AH activity, and seizure events in a rat model.
Main Methods:
- Kainate-induced seizures were modeled in rats.
- Platelet-activating factor acetylhydrolase (PAF-AH) enzymatic activity was measured.
- LIS1 and its alpha2 catalytic subunit expression levels were analyzed in the dentate gyrus.
- Microtubule-associated fractions were examined for LIS1 isoforms.
Main Results:
- PAF-AH activity significantly decreased within 30 minutes of seizure induction, serving as a sensitive seizure indicator.
- LIS1 expression in the dentate gyrus mirrored PAF-AH activity changes.
- A novel, higher-mobility LIS1 isoform, enriched in microtubules, was detected post-seizure.
- Expression of the alpha2 catalytic subunit of PAF-AH was dramatically altered.
Conclusions:
- LIS1 expression is a critical regulator of PAF-AH activity.
- Reduced LIS1 levels in lissencephaly patients may increase seizure susceptibility.
- The identified LIS1 isoform may play a role in the cellular response to seizures.
Abstract:
Lissencephaly patients are born with severe brain malformations and suffer from recurrent seizures. LIS1, the gene mutated in isolated lissencephaly patients, is a subunit of the heterotrimeric cytosolic enzyme platelet-activating factor acetylhydrolase (PAF-AH), interacts with tubulin, and affects microtubule dynamics. In order to gain molecular insights into the possible involvement of LIS1 in seizures in lissencephaly patients, we induced seizures in rats by injection of kainate. PAF-AH activity was markedly reduced as early as 30 min following initiation of seizures, making this parameter a sensitive indicator of seizure events. PAF-AH activity returned to and surpassed control values 1 week following initiation of seizures. Expression of LIS1 in the dentate gyrus changed significantly in a manner similar to that of PAF-AH enzymatic activity. This is the first correlation found between LIS1 expression and PAF-AH activity. Furthermore, the expression of the alpha2 catalytic subunit, which is the major PAF-AH catalytic subunit in rat adult brain, changed in a dramatic fashion. An additional higher-mobility LIS1 cross-reactive band was detected in samples isolated a week following seizure occurrence. This LIS1 isoform was enriched in the microtubule-associated fraction. We propose that LIS1 expression is an important factor in regulation of PAF-AH activity. We postulate that reductions in LIS1 protein levels found in lissencephaly patients may render them more susceptible to seizures.
