RRC ID 37535
著者 Nishitani A, Tanaka M, Shimizu S, Kunisawa N, Yokoe M, Yoshida Y, Suzuki T, Sakuma T, Yamamoto T, Kuwamura M, Takenaka S, Ohno Y, Kuramoto T.
タイトル Involvement of aspartoacylase in tremor expression in rats.
ジャーナル Exp Anim
Abstract 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.
巻・号 65(3)
ページ 293-301
公開日 2016-7-29
DOI 10.1538/expanim.16-0007
PMID 27026062
PMC PMC4976243
MeSH Amidohydrolases / deficiency Amidohydrolases / genetics* Animals Aspartic Acid / analogs & derivatives Aspartic Acid / urine Central Nervous System / pathology Codon, Nonsense* Disease Models, Animal Epistasis, Genetic Essential Tremor / genetics* Essential Tremor / pathology Exons / genetics Gene Deletion* Genetic Association Studies* Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / deficiency Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / genetics Mice Mutation, Missense* Potassium Channels / deficiency Potassium Channels / genetics Rats Rats, Mutant Strains
IF 1.574
引用数 10
WOS 分野 VETERINARY SCIENCES ZOOLOGY
リソース情報
ラット F344-Aspaem31Kyo (strainID=1206) F344-Aspaem34Kyo (strainID=1207)