Ultrastructural features of canine neuroaxonal dystrophy in a Papillon dog

Tanaka, Miyuu; Yamaguchi, Shinobu; Akiyoshi, Hideo; Tsuboi, Masamichi; Uchida, Kazuyuki; Izawa, Takeshi; Yamate, Jyoji; Kuwamura, Mitsuru

doi:10.1292/jvms.17-0487

Cited by 5 publications

(5 citation statements)

References 25 publications

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“…Swollen axons sometimes lacked a myelin sheath. These findings were consistent with the ultrastructural observations previously reported in patients and animals with NAD ( Yagishita and Kimura, 1974 ; de Leon and Mitchell, 1985 ; Beck et al, 2011 ; Tanaka et al, 2017 ).…”

Section: Resultssupporting

confidence: 93%

“…The F344- kk / kk rats exhibited the hind limb gait abnormality and the axonal swelling in histopathology, also called the spheroid ( Figure 1 ). Since the lower limb ataxia is a major clinical symptom of the NAD and the spheroid is a hallmark of the NAD ( Bouley et al, 2006 ; Tanaka et al, 2017 ), we diagnosed F344- kk / kk rats as NAD. The spheroids distributed throughout the CNS and predominantly located in the sensory tracts associated with proprioceptive sense (deep sensation).…”

Section: Discussionmentioning

confidence: 99%

“…In animals, inherited NAD has been identified in various species including dogs ( Fyfe et al, 2011 ; Hahn et al, 2015 ; Tanaka et al, 2017 ; Tsuboi et al, 2017 ; Lucot et al, 2018 ), cats ( Carmichael et al, 1993 ), horses ( Hales et al, 2020 ), sheep ( Letko et al, 2021 ), and laboratory mice ( Saigoh et al, 1999 ). In dogs, different genes have been identified as causative genes of NAD.…”

Section: Introductionmentioning

confidence: 99%

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A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats

Tanaka,

Fujikawa,

Sekiguchi

et al. 2024

Front. Neurosci.

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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.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats

Tanaka,

Fujikawa,

Sekiguchi

et al. 2024

Front. Neurosci.

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“…Canine NAD has previously been reported in both mixed breed and purebred dogs, including Rottweiler (Lucot et al 2018), Spanish Water dog (Hahn et al 2015), Collie (Clark et al 1982), Chihuahua (Degl'Innocenti et al 2017), Jack Russell Terrier (Sacre et al 1993), Dachshund-cross dog (Pintus et al 2016), Schnauzer-Beagle cross (Fyfe et al 2011) and Papillons (Tanaka et al 2017;Tsuboi et al 2017). To date, four breed-speci c forms have the underlying genetic cause identi ed.…”

Section: Introductionmentioning

confidence: 95%

RNF170 frameshift deletion in Miniature American Shepherd dogs with neuroaxonal dystrophy provides a naturally occurring model for human RNF170 phenotypic spectrum

Cook,

Schwarz,

Guevar

et al. 2024

Preprint

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Neuroaxonal dystrophy (NAD) is a group of inherited neurodegenerative disorders characterized primarily by the presence of spheroids (swollen axons) throughout the central nervous system. In humans, NAD is heterogeneous, both clinically and genetically. NAD has also been described to naturally occur in large animal models, such as dogs. A newly recognized disorder in Miniature American Shepherd dogs (MAS), consisting of a slowly progressive neurodegenerative syndrome, was diagnosed as NAD via histopathology. Affected dogs were typically young adults and displayed an abnormal gait characterized by pelvic limb weakness and ataxia. A combined GWAS and autozygosity mapping approach, together with whole-genome sequencing, identified the underlying genetic cause as a 1-bp deletion in RNF170 (ring finger protein 170), which perfectly segregates in an autosomal recessive pattern. This deletion is predicted to create a frameshift (XM_038559916.1:c.367delG) and early truncation of the RNF170 protein (XP_038415844.1:(p.Ala123Glnfs*11). A significant LOD score of 9.70 in an extended pedigree confirms the linkage of the deletion variant with the canine phenotype. Several RNF170 variants have been identified in human patients with analogous clinical syndromes, indicating that this novel MAS NAD serves as an excellent large animal model for equivalent human diseases, particularly since affected dogs demonstrate a relatively long lifespan, which represents an opportunity for therapeutic trials. The age of this canine RNF170 variant is estimated at approximately 30 years, before the reproductive isolation of the MAS breed. This carries implications for the standard Australian Shepherd, the breed from which MAS were developed.

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“…Axonal dystrophy is a known age-related spontaneous finding in the nervous system, especially brain, and has been reported in many animal species and humans. [1][2][3][4][13][14][15][16][17][18][19][20] Increased AD numbers have been seen in several breeds of dogs due to autosomal mutations leading to progressive degeneration of central and/or peripheral neurons [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] ; vitamin E deficiency, 4,38,39 presumably leading to increased oxidative stress 39 ; or exposure to toxicants that cause cytoskeletal cross-linking among other mechanisms of toxicity. [40][41][42][43][44][45][46][47][48][49] Axonal dystrophy also has been described in dogs with chronic wasting diseases (eg, filariasis, tumor-related cachexia).…”

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confidence: 99%

Spontaneous Axonal Dystrophy in the Brain and Spinal Cord in Naïve Beagle Dogs

et al. 2020

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Axonal dystrophy (AD) is a common age-related neurohistological finding in vertebrates that can be congenital or induced by xenobiotics, vitamin E deficiency, or trauma/compression. To understand the incidence and location of AD as a background finding in Beagle dogs used in routine toxicity studies, we examined central nervous system (CNS) and selected peripheral nervous system (PNS) tissues in twenty 18- to 24-month-old and ten 4- to 5-year-old control males and females. Both sexes were equally affected. The cuneate, gracile, and cochlear nuclei and the cerebellar white matter (rostral vermis) were the most common locations for AD. Incidence of AD increased with age in the cuneate nucleus, cerebellar white matter (rostral vermis), trigeminal nuclei/tracts, and lumbar spinal cord. Axonal dystrophy in the CNS was not accompanied by neuronal degeneration/necrosis, nerve fiber degeneration, and/or glial reaction. Axonal dystrophy was not observed in the PNS (sciatic nerve, vagus nerve branches, or gastrointestinal mural autonomic plexuses).

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Ultrastructural features of canine neuroaxonal dystrophy in a Papillon dog

Cited by 5 publications

References 25 publications

A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats

A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats

RNF170 frameshift deletion in Miniature American Shepherd dogs with neuroaxonal dystrophy provides a naturally occurring model for human RNF170 phenotypic spectrum

Spontaneous Axonal Dystrophy in the Brain and Spinal Cord in Naïve Beagle Dogs

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