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Involvement of aspartoacylase in tremor expression in rats
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-activate...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Japanese Association for Laboratory Animal Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976243/ https://www.ncbi.nlm.nih.gov/pubmed/27026062 http://dx.doi.org/10.1538/expanim.16-0007 |
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author | Nishitani, Ai Tanaka, Miyuu Shimizu, Saki Kunisawa, Naofumi Yokoe, Mayuko Yoshida, Yusaku Suzuki, Toshiro Sakuma, Tetsushi Yamamoto, Takashi Kuwamura, Mitsuru Takenaka, Shigeo Ohno, Yukihiro Kuramoto, Takashi |
author_facet | Nishitani, Ai Tanaka, Miyuu Shimizu, Saki Kunisawa, Naofumi Yokoe, Mayuko Yoshida, Yusaku Suzuki, Toshiro Sakuma, Tetsushi Yamamoto, Takashi Kuwamura, Mitsuru Takenaka, Shigeo Ohno, Yukihiro Kuramoto, Takashi |
author_sort | Nishitani, Ai |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4976243 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Japanese Association for Laboratory Animal Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-49762432016-08-09 Involvement of aspartoacylase in tremor expression in rats Nishitani, Ai Tanaka, Miyuu Shimizu, Saki Kunisawa, Naofumi Yokoe, Mayuko Yoshida, Yusaku Suzuki, Toshiro Sakuma, Tetsushi Yamamoto, Takashi Kuwamura, Mitsuru Takenaka, Shigeo Ohno, Yukihiro Kuramoto, Takashi Exp Anim Original 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. Japanese Association for Laboratory Animal Science 2016-03-30 2016 /pmc/articles/PMC4976243/ /pubmed/27026062 http://dx.doi.org/10.1538/expanim.16-0007 Text en ©2016 Japanese Association for Laboratory Animal Science http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. |
spellingShingle | Original Nishitani, Ai Tanaka, Miyuu Shimizu, Saki Kunisawa, Naofumi Yokoe, Mayuko Yoshida, Yusaku Suzuki, Toshiro Sakuma, Tetsushi Yamamoto, Takashi Kuwamura, Mitsuru Takenaka, Shigeo Ohno, Yukihiro Kuramoto, Takashi Involvement of aspartoacylase in tremor expression in rats |
title | Involvement of aspartoacylase in tremor expression in rats |
title_full | Involvement of aspartoacylase in tremor expression in rats |
title_fullStr | Involvement of aspartoacylase in tremor expression in rats |
title_full_unstemmed | Involvement of aspartoacylase in tremor expression in rats |
title_short | Involvement of aspartoacylase in tremor expression in rats |
title_sort | involvement of aspartoacylase in tremor expression in rats |
topic | Original |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976243/ https://www.ncbi.nlm.nih.gov/pubmed/27026062 http://dx.doi.org/10.1538/expanim.16-0007 |
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