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- / rats with hind limb gait abnormalities and ataxia from a young age...

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Veröffentlicht in:Frontiers in neuroscience 2024-02, Vol.18, p.1263724-1263724
Hauptverfasser: Tanaka, Miyuu, Fujikawa, Ryoko, Sekiguchi, Takahiro, Hernandez, Jason, Johnson, Oleta T, Tanaka, Daisuke, Kumafuji, Kenta, Serikawa, Tadao, Hoang Trung, Hieu, Hattori, Kosuke, Mashimo, Tomoji, Kuwamura, Mitsuru, Gestwicki, Jason E, Kuramoto, Takashi
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Sprache:eng
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Zusammenfassung: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- / 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- / 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- / rats were diagnosed with NAD. By a positional cloning approach, we identified a missense mutation (V95E) in the (heat shock protein family A (Hsp70) member 8) gene located on chromosome 8 of the F344- / rat genome. Furthermore, we developed the knock-in (KI) rats with the V95E mutation using the CRISPR-Cas system. Homozygous -KI rats exhibited ataxia and axonal spheroids similar to those of F344- / 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 , which suggests the functional deficit in the V95E HSC70. Together, our findings provide the first evidence that the genetic alteration of the gene caused NAD in mammals.
ISSN:1662-4548
1662-453X
1662-453X
DOI:10.3389/fnins.2024.1263724