{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T08:35:19Z","timestamp":1773304519978,"version":"3.50.1"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T00:00:00Z","timestamp":1707177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009583","name":"Morinaga Foundation for Health and Nutrition","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009583","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>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-<jats:italic>kk<\/jats:italic>\/<jats:italic>kk<\/jats:italic> 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-<jats:italic>kk<\/jats:italic>\/<jats:italic>kk<\/jats:italic> 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-<jats:italic>kk<\/jats:italic>\/<jats:italic>kk<\/jats:italic> rats were diagnosed with NAD. By a positional cloning approach, we identified a missense mutation (V95E) in the <jats:italic>Hspa8<\/jats:italic> (heat shock protein family A (Hsp70) member 8) gene located on chromosome 8 of the F344-<jats:italic>kk<\/jats:italic>\/<jats:italic>kk<\/jats:italic> rat genome. Furthermore, we developed the <jats:italic>Hspa8<\/jats:italic> knock-in (KI) rats with the V95E mutation using the CRISPR-Cas system. Homozygous <jats:italic>Hspa8<\/jats:italic>-KI rats exhibited ataxia and axonal spheroids similar to those of F344-<jats:italic>kk<\/jats:italic>\/<jats:italic>kk<\/jats:italic> 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 <jats:italic>in vitro<\/jats:italic>, which suggests the functional deficit in the V95E HSC70. Together, our findings provide the first evidence that the genetic alteration of the <jats:italic>Hspa8<\/jats:italic> gene caused NAD in mammals.<\/jats:p>","DOI":"10.3389\/fnins.2024.1263724","type":"journal-article","created":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T04:33:15Z","timestamp":1707193995000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats"],"prefix":"10.3389","volume":"18","author":[{"given":"Miyuu","family":"Tanaka","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryoko","family":"Fujikawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahiro","family":"Sekiguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason","family":"Hernandez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oleta T.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenta","family":"Kumafuji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadao","family":"Serikawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hieu","family":"Hoang Trung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kosuke","family":"Hattori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoji","family":"Mashimo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitsuru","family":"Kuwamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason E.","family":"Gestwicki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Kuramoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,2,6]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"11411","DOI":"10.1523\/JNEUROSCI.0345-11.2011","article-title":"Neuroaxonal dystrophy in calcium-independent phospholipase A2beta deficiency results from insufficient remodeling and degeneration of mitochondrial and presynaptic membranes","volume":"31","author":"Beck","year":"2011","journal-title":"J. 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