Shmueli O, Cahana A, Reiner O
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.
J Neurosci Res. 1999 Jul 15;57(2):176-84. doi: 10.1002/(SICI)1097-4547(19990715)57:2<176::AID-JNR3>3.0.CO;2-U.
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.
无脑回畸形患者出生时伴有严重的脑畸形，并患有反复发作的癫痫。LIS1基因在孤立性无脑回畸形患者中发生突变，它是异三聚体细胞溶质酶血小板活化因子乙酰水解酶（PAF-AH）的一个亚基，与微管蛋白相互作用，并影响微管动力学。为了从分子层面深入了解LIS1在无脑回畸形患者癫痫发作中可能的作用，我们通过注射红藻氨酸在大鼠中诱发癫痫发作。癫痫发作开始后30分钟，PAF-AH活性就显著降低，这使得该参数成为癫痫发作事件的一个敏感指标。癫痫发作开始1周后，PAF-AH活性恢复并超过了对照值。齿状回中LIS1的表达变化与PAF-AH酶活性的变化方式相似，具有显著差异。这是首次发现LIS1表达与PAF-AH活性之间的相关性。此外，大鼠成年大脑中主要的PAF-AH催化亚基α2催化亚基的表达发生了显著变化。癫痫发作一周后分离的样本中检测到一条额外的高迁移率LIS1交叉反应带。这种LIS1同工型在微管相关组分中富集。我们认为LIS1表达是调节PAF-AH活性的一个重要因素。我们推测，无脑回畸形患者中发现的LIS1蛋白水平降低可能使他们更容易发生癫痫发作。
