Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Essential tremor (ET) is a common movement disorder with a poorly understood etiology. The TRM/Kyo mutant rat, showing spontaneous tremor, is an animal model of ET. Recently, we demonstrated that tremors in these rats emerge when two mutant loci, a missense mutation in the hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (Hcn1) and the tremor (tm) deletion, are present simultaneously. However, we did not identify which gene within the tm deletion causes tremor expression in TRM/Kyo rats. A strong candidate among the 13 genes within the tm deletion is aspartoacylase (Aspa), because some Aspa-knockout mouse strains show tremor. Here, we generated Aspa-knockout rats using transcription activator-like effector nuclease technology and produced Aspa/Hcn1 double-mutant rats by crossing Aspa-knockout rats with Hcn1-mutant rats. The Aspa-knockout rats carried nonsense mutations in exon 4; and ASPA proteins were not detectable in their brain extracts. They showed elevated levels of N-acetyl-L-aspartate (NAA) in urine and spongy vacuolation and abnormal myelination in the central nervous system, but no tremor. By contrast, Aspa/Hcn1 double-mutant rats spontaneously showed tremors resembling those in TRM/Kyo rats, and the tremor was suppressed by drugs therapeutic for ET but not for parkinsonian tremor. These findings indicated that the lack of the Aspa gene caused tremor expression in TRM/Kyo rats. Our animal model suggested that the interaction of NAA accumulation due to ASPA deficiency with an unstable neuronal membrane potential caused by HCN1 deficiency was involved in tremor development.
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PMID:Involvement of aspartoacylase in tremor expression in rats. 2702 62

We recently demonstrated that aspartoacylase (Aspa) and hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (Hcn1) genes were causative of essential tremor (ET) in rats. This finding was obtained using Aspaem34Kyo/Hcn1A354V double-mutant rats, but they were bred on a heterogeneous genetic background of two strains, F344 and WTC. Here, we developed an Aspaem34Kyo/Hcn1em1Kyo double-knockout rat strain with a homogenous F344 genetic background and studied the ability of glutamate receptor antagonists to suppress ET. The F344-Aspa/Hcn1 double-knockout rats exhibited spontaneous, intense body tremor equivalent to that in the double-mutant rats. N-acetyl-aspartate (NAA), a substrate of ASPA, showed accumulation in all brain regions and in the spinal cord. However, N-acetyl-aspartyl-glutamate (NAAG), which is derived from NAA and interacts with glutamatergic receptors, was decreased in the medulla oblongata of the double-knockout rats. The tremor was suppressed by 3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid, an N-methyl-D-aspartate (NMDA) receptor antagonist, in F344-Aspa/Hcn1 double-knockout rats. The non-NMDA glutamate receptor antagonist NBQX weakly inhibited the tremor, while the metabotropic glutamate receptor antagonist LY341495 showed no effect. In addition, both NR2B subunit-specific (Ro 25-6981) and NR2C/NR2D subunit-specific (cis-piperidine dicarboxylic acid) NMDA receptor antagonists suppressed the tremor. These data indicated that the pathogenesis of tremor in Aspa/Hcn1 double-knockout rats involved ionotropic glutamate receptors, particularly NMDA receptors.
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PMID:Involvement of NMDA receptors in tremor expression in Aspa/Hcn1 double-knockout rats. 3250 87