title: Involvement of aspartoacylase in tremor expression in rats.
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.
authors.affiliation: Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshida-konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Nishitani
authors.forename: Miyuu
authors.initials: M
authors.lastname: Tanaka
authors.forename: Saki
authors.initials: S
authors.lastname: Shimizu
authors.forename: Naofumi
authors.initials: N
authors.lastname: Kunisawa
authors.forename: Mayuko
authors.initials: M
authors.lastname: Yokoe
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Toshiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Sakuma
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kuwamura
authors.forename: Shigeo
authors.initials: S
authors.lastname: Takenaka
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Ohno
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuramoto
mesh_terms: D000581:Amidohydrolases / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000652:urine; D002490:Central Nervous System / Q000473:pathology; D018389:Codon, Nonsense; D004195:Disease Models, Animal; D004843:Epistasis, Genetic; D020329:Essential Tremor / Q000235:genetics* / Q000473:pathology; D005091:Exons / Q000235:genetics; D017353:Gene Deletion; D056726:Genetic Association Studies; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000172:deficiency / Q000235:genetics; D051379:Mice; D020125:Mutation, Missense; D015221:Potassium Channels / Q000172:deficiency / Q000235:genetics; D051381:Rats; D011922:Rats, Mutant Strains
chemical_list: D018389:Codon, Nonsense; C578667:Hcn1 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D001224:Aspartic Acid; C000179:N-acetylaspartate; D000581:Amidohydrolases; C019751:aspartoacylase