Spontaneous Murine Neuroaxonal Dystrophy: a Model of Infantile Neuroaxonal Dystrophy

Bouley, Donna M.; McIntire, Jennifer J.; Harris, Brent T.; Tolwani, Ravi; Otto, G; Hayflick, SJ

doi:10.1016/j.jcpa.2005.10.002

Cited by 17 publications

(21 citation statements)

References 39 publications

(56 reference statements)

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“…4,5 Degeneration commences in the distal axon and progresses proximally, resulting in eventual death of the neuronal cell body. 4,5 Degeneration commences in the distal axon and progresses proximally, resulting in eventual death of the neuronal cell body.…”

Section: Discussionmentioning

confidence: 99%

Axonal Spheroid Accumulation In the Brainstem and Spinal Cord of A Young Angus Cow with Ataxia

et al. 2015

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The topographical distribution of axonal spheroids in the brain and spinal cord in this bovine case closely resembled that found in the ovine neurodegenerative disorder termed NAD, in which axonal swellings are the major pathological feature. This appears to be the first reported case of this type of NAD in cattle. The aetiology of the spheroidal aggregations in this case was not determined. There was no evidence from the case history or neuropathology to indicate whether the axonal spheroids in this case involved an acquired or heritable aetiology.

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Section: Discussionmentioning

confidence: 99%

Axonal Spheroid Accumulation In the Brainstem and Spinal Cord of A Young Angus Cow with Ataxia

et al. 2015

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“…A mutation in one of these mouse lines has been identified in the Uchl1 gene, which encodes a ubiquitin carboxy-terminal hydrolase that may regulate levels of free monomeric ubiquitin, 42 providing further support for the hypothesis that dysregulated protein ubiquitination or failed targeting of ubiquitinated proteins might play a central role in neuroaxonal injury and degeneration. Identification of the genetic defects in other mouse models 38,39 might also provide further insight into pathways involved in these pathological processes.…”

Section: Discussionmentioning

confidence: 99%

Disrupted Membrane Homeostasis and Accumulation of Ubiquitinated Proteins in a Mouse Model of Infantile Neuroaxonal Dystrophy Caused by PLA2G6 Mutations

Malik

Turk

Mancuso

et al. 2008

The American Journal of Pathology

148

129

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Mutations in the PLA2G6 gene, which encodes group VIA calcium-independent phospholipase A2 (iPLA 2 ␤), were recently identified in patients with infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation. A pathological hallmark of these childhood neurodegenerative diseases is the presence of distinctive spheroids in distal axons that contain accumulated membranes. We used iPLA 2 ␤-KO mice generated by homologous recombination to investigate neurodegenerative consequences of PLA2G6 mutations. iPLA 2 ␤-KO mice developed age-dependent neurological impairment that was evident in rotarod, balance, and climbing tests by 13 months of age. The primary abnormality underlying this neurological impairment was the formation of spheroids containing tubulovesicular membranes remarkably similar to human INAD. Spheroids were strongly labeled with anti-ubiquitin antibodies. Accumulation of ubiquitinated protein in spheroids was evident in some brain regions as early as 4 months of age, and the onset of motor impairment correlated with a dramatic increase in ubiquitin-positive spheroids throughout the neuropil in nearly all brain regions. Furthermore accumulating ubiquitinated proteins were observed primarily in insoluble fractions of brain tissue, implicating protein aggregation in this pathogenic process. These results indicate that loss of iPLA 2 ␤ causes age-dependent impairment of axonal membrane homeostasis and protein degradation pathways, leading to age-dependent neurological impairment. iPLA 2 ␤-KO mice will be useful for further studies of pathogenesis and experimental interventions in INAD and neurodegeneration with brain iron accumulation.

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“…Neuroaxonal dystrophy (NAD) is a group of rare, heterogeneous inherited neurodegenerative disorders that has been described in various mammalian species, including humans [7–8], dogs [9–21], sheep [22–24], cattle [25], horses [26–28], cats [29–30], rabbits [31], rats [32], and mice [33–37]. Although they all share a characteristic pathological feature, i .…”

Section: Introductionmentioning

confidence: 99%

Identification of the PLA2G6 c.1579G>A Missense Mutation in Papillon Dog Neuroaxonal Dystrophy Using Whole Exome Sequencing Analysis

Tsuboi

Watanabe

Nibe³

et al. 2017

PLoS ONE

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Whole exome sequencing (WES) has become a common tool for identifying genetic causes of human inherited disorders, and it has also recently been applied to canine genome research. We conducted WES analysis of neuroaxonal dystrophy (NAD), a neurodegenerative disease that sporadically occurs worldwide in Papillon dogs. The disease is considered an autosomal recessive monogenic disease, which is histopathologically characterized by severe axonal swelling, known as “spheroids,” throughout the nervous system. By sequencing all eleven DNA samples from one NAD-affected Papillon dog and her parents, two unrelated NAD-affected Papillon dogs, and six unaffected control Papillon dogs, we identified 10 candidate mutations. Among them, three candidates were determined to be “deleterious” by in silico pathogenesis evaluation. By subsequent massive screening by TaqMan genotyping analysis, only the PLA2G6 c.1579G>A mutation had an association with the presence or absence of the disease, suggesting that it may be a causal mutation of canine NAD. As a human homologue of this gene is a causative gene for infantile neuroaxonal dystrophy, this canine phenotype may serve as a good animal model for human disease. The results of this study also indicate that WES analysis is a powerful tool for exploring canine hereditary diseases, especially in rare monogenic hereditary diseases.

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Spontaneous Murine Neuroaxonal Dystrophy: a Model of Infantile Neuroaxonal Dystrophy

Cited by 17 publications

References 39 publications

Axonal Spheroid Accumulation In the Brainstem and Spinal Cord of A Young Angus Cow with Ataxia

Axonal Spheroid Accumulation In the Brainstem and Spinal Cord of A Young Angus Cow with Ataxia

Disrupted Membrane Homeostasis and Accumulation of Ubiquitinated Proteins in a Mouse Model of Infantile Neuroaxonal Dystrophy Caused by PLA2G6 Mutations

Identification of the PLA2G6 c.1579G>A Missense Mutation in Papillon Dog Neuroaxonal Dystrophy Using Whole Exome Sequencing Analysis

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