A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats
Neuroaxonal dystrophy (NAD) is a neurodegenerative disease characterized by spheroid (swollen axon) formation in the nervous system. In the present study, we focused on a newly established autosomal recessive mutant strain of F344-kk/kk rats with hind limb gait abnormalities and ataxia from a young...
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2024.1263724/full |
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| author | Miyuu Tanaka Miyuu Tanaka Ryoko Fujikawa Takahiro Sekiguchi Jason Hernandez Oleta T. Johnson Daisuke Tanaka Kenta Kumafuji Tadao Serikawa Hieu Hoang Trung Kosuke Hattori Tomoji Mashimo Mitsuru Kuwamura Jason E. Gestwicki Takashi Kuramoto Takashi Kuramoto |
| author_facet | Miyuu Tanaka Miyuu Tanaka Ryoko Fujikawa Takahiro Sekiguchi Jason Hernandez Oleta T. Johnson Daisuke Tanaka Kenta Kumafuji Tadao Serikawa Hieu Hoang Trung Kosuke Hattori Tomoji Mashimo Mitsuru Kuwamura Jason E. Gestwicki Takashi Kuramoto Takashi Kuramoto |
| author_sort | Miyuu Tanaka |
| collection | DOAJ |
| description | Neuroaxonal dystrophy (NAD) is a neurodegenerative disease characterized by spheroid (swollen axon) formation in the nervous system. In the present study, we focused on a newly established autosomal recessive mutant strain of F344-kk/kk rats with hind limb gait abnormalities and ataxia from a young age. Histopathologically, a number of axonal spheroids were observed throughout the central nervous system, including the spinal cord (mainly in the dorsal cord), brain stem, and cerebellum in F344-kk/kk rats. Transmission electron microscopic observation of the spinal cord revealed accumulation of electron-dense bodies, degenerated abnormal mitochondria, as well as membranous or tubular structures in the axonal spheroids. Based on these neuropathological findings, F344-kk/kk rats were diagnosed with NAD. By a positional cloning approach, we identified a missense mutation (V95E) in the Hspa8 (heat shock protein family A (Hsp70) member 8) gene located on chromosome 8 of the F344-kk/kk rat genome. Furthermore, we developed the Hspa8 knock-in (KI) rats with the V95E mutation using the CRISPR-Cas system. Homozygous Hspa8-KI rats exhibited ataxia and axonal spheroids similar to those of F344-kk/kk rats. The V95E mutant HSC70 protein exhibited the significant but modest decrease in the maximum hydrolysis rate of ATPase when stimulated by co-chaperons DnaJB4 and BAG1 in vitro, which suggests the functional deficit in the V95E HSC70. Together, our findings provide the first evidence that the genetic alteration of the Hspa8 gene caused NAD in mammals. |
| first_indexed | 2024-03-08T05:00:45Z |
| format | Article |
| id | doaj.art-b5bf84a562e746e195914f25780aba1c |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-03-08T05:00:45Z |
| publishDate | 2024-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Neuroscience |
| spelling | doaj.art-b5bf84a562e746e195914f25780aba1c2024-02-07T12:08:28ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2024-02-011810.3389/fnins.2024.12637241263724A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in ratsMiyuu Tanaka0Miyuu Tanaka1Ryoko Fujikawa2Takahiro Sekiguchi3Jason Hernandez4Oleta T. Johnson5Daisuke Tanaka6Kenta Kumafuji7Tadao Serikawa8Hieu Hoang Trung9Kosuke Hattori10Tomoji Mashimo11Mitsuru Kuwamura12Jason E. Gestwicki13Takashi Kuramoto14Takashi Kuramoto15Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, JapanLaboratory of Veterinary Pathology, Graduate School of Veterinary Science, Osaka Metropolitan University, Izumisano, Osaka, JapanLaboratory of Veterinary Pathology, Graduate School of Veterinary Science, Osaka Metropolitan University, Izumisano, Osaka, JapanLaboratory of Veterinary Pathology, Graduate School of Veterinary Science, Osaka Metropolitan University, Izumisano, Osaka, JapanDepartment of Pharmaceutical Chemistry and the Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, United StatesDepartment of Pharmaceutical Chemistry and the Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, United StatesInstitute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, JapanInstitute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, JapanInstitute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, JapanDepartment of Animal Science, Faculty of Agriculture, Tokyo University of Agriculture, Atsugi, Kanagawa, JapanDivision of Animal Genetics, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, JapanDivision of Animal Genetics, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, JapanLaboratory of Veterinary Pathology, Graduate School of Veterinary Science, Osaka Metropolitan University, Izumisano, Osaka, JapanDepartment of Pharmaceutical Chemistry and the Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, United StatesInstitute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, JapanDepartment of Animal Science, Faculty of Agriculture, Tokyo University of Agriculture, Atsugi, Kanagawa, JapanNeuroaxonal dystrophy (NAD) is a neurodegenerative disease characterized by spheroid (swollen axon) formation in the nervous system. In the present study, we focused on a newly established autosomal recessive mutant strain of F344-kk/kk rats with hind limb gait abnormalities and ataxia from a young age. Histopathologically, a number of axonal spheroids were observed throughout the central nervous system, including the spinal cord (mainly in the dorsal cord), brain stem, and cerebellum in F344-kk/kk rats. Transmission electron microscopic observation of the spinal cord revealed accumulation of electron-dense bodies, degenerated abnormal mitochondria, as well as membranous or tubular structures in the axonal spheroids. Based on these neuropathological findings, F344-kk/kk rats were diagnosed with NAD. By a positional cloning approach, we identified a missense mutation (V95E) in the Hspa8 (heat shock protein family A (Hsp70) member 8) gene located on chromosome 8 of the F344-kk/kk rat genome. Furthermore, we developed the Hspa8 knock-in (KI) rats with the V95E mutation using the CRISPR-Cas system. Homozygous Hspa8-KI rats exhibited ataxia and axonal spheroids similar to those of F344-kk/kk rats. The V95E mutant HSC70 protein exhibited the significant but modest decrease in the maximum hydrolysis rate of ATPase when stimulated by co-chaperons DnaJB4 and BAG1 in vitro, which suggests the functional deficit in the V95E HSC70. Together, our findings provide the first evidence that the genetic alteration of the Hspa8 gene caused NAD in mammals.https://www.frontiersin.org/articles/10.3389/fnins.2024.1263724/fullanimal modelaxonHspa8neuroaxonal dystrophyratspheroid |
| spellingShingle | Miyuu Tanaka Miyuu Tanaka Ryoko Fujikawa Takahiro Sekiguchi Jason Hernandez Oleta T. Johnson Daisuke Tanaka Kenta Kumafuji Tadao Serikawa Hieu Hoang Trung Kosuke Hattori Tomoji Mashimo Mitsuru Kuwamura Jason E. Gestwicki Takashi Kuramoto Takashi Kuramoto A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats Frontiers in Neuroscience animal model axon Hspa8 neuroaxonal dystrophy rat spheroid |
| title | A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats |
| title_full | A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats |
| title_fullStr | A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats |
| title_full_unstemmed | A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats |
| title_short | A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats |
| title_sort | missense mutation in the hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats |
| topic | animal model axon Hspa8 neuroaxonal dystrophy rat spheroid |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2024.1263724/full |
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