Giant Axonal Neuropathy: Clinical, Electrophysiologic, and Neuropathologic Features in Two Siblings

Kumar, Kusum; Barre, Peter S.; Nigro, Michael A.; Jones, M. Z.

doi:10.1177/088307389000500316

Cited by 31 publications

(19 citation statements)

References 24 publications

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“…To assess whether gigaxonin ablation produces, as in humans, a neuronal loss in the ventral horn of the spinal cord [32], a decrease of axonal density in peripheral nerves and a presence of giant axons [4,5], we examined cross sections of spinal cords and proximal/distal nerves from 48 week-old GAN ex3-5 mice. Regardless of the genetic background, the number of motor neurons in lumbar spinal cord did not differ between WT and KO mice (Figure 4A and Additional file 2).…”

Section: Resultsmentioning

confidence: 99%

“…Whereas the rare autopsies of GAN patients have revealed a loss of neurons in the ventral horn of the spinal cord [32], no motor neuron degeneration was observed in our GAN ex3-5 model, in agreement with observations in the GAN ex1 model at 48 weeks of age [31]. The decrease in the axonal density in proximal and distal nerves of our GAN ex3-5 129/SvJ mice was constant but approached statistical significance and would have required an increase in animal numbers.…”

Section: Discussionmentioning

confidence: 99%

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Sensory-motor deficits and neurofilament disorganization in gigaxonin-null mice

Ganay

Boizot

Burrer

et al. 2011

Mol Neurodegeneration

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BackgroundGiant Axonal Neuropathy (GAN) is a fatal neurodegenerative disorder with early onset characterized by a severe deterioration of the peripheral and central nervous system, involving both the motor and the sensory tracts and leading to ataxia, speech defect and intellectual disabilities. The broad deterioration of the nervous system is accompanied by a generalized disorganization of the intermediate filaments, including neurofilaments in neurons, but the implication of this defect in disease onset or progression remains unknown. The identification of gigaxonin, the substrate adaptor of an E3 ubiquitin ligase, as the defective protein in GAN allows us to now investigate the crucial role of the gigaxonin-E3 ligase in sustaining neuronal and intermediate filament integrity. To study the mechanisms controlled by gigaxonin in these processes and to provide a relevant model to test the therapeutic approaches under development for GAN, we generated a Gigaxonin-null mouse by gene targeting.ResultsWe investigated for the first time in Gigaxonin-null mice the deterioration of the motor and sensory functions over time as well as the spatial disorganization of neurofilaments. We showed that gigaxonin depletion in mice induces mild but persistent motor deficits starting at 60 weeks of age in the 129/SvJ-genetic background, while sensory deficits were demonstrated in C57BL/6 animals. In our hands, another gigaxonin-null mouse did not display the early and severe motor deficits reported previously. No apparent neurodegeneration was observed in our knock-out mice, but dysregulation of neurofilaments in proximal and distal axons was massive. Indeed, neurofilaments were not only more abundant but they also showed the abnormal increase in diameter and misorientation that are characteristics of the human pathology.ConclusionsTogether, our results show that gigaxonin depletion in mice induces mild motor and sensory deficits but recapitulates the severe neurofilament dysregulation seen in patients. Our model will allow investigation of the role of the gigaxonin-E3 ligase in organizing neurofilaments and may prove useful in understanding the pathological processes engaged in other neurodegenerative disorders characterized by accumulation of neurofilaments and dysfunction of the Ubiquitin Proteasome System, such as Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's and Parkinson's diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sensory-motor deficits and neurofilament disorganization in gigaxonin-null mice

Ganay

Boizot

Burrer

et al. 2011

Mol Neurodegeneration

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“…The most severely affected areas include the corticospinal tracts, the middle cerebellar peduncles, the posterior columns, and the oligocerebellar connections [13]. Loss of Purkinje cells and other neuronal cells has been reported [14]. Analysis of GAN patient fibroblasts in culture showed apparently normal levels of vimentin with biochemical properties that were indistinguishable from normal, leading to the hypothesis that GAN is the consequence of intermediate filament disorganization [15].…”

Section: Pathologymentioning

confidence: 98%

Giant axonal neuropathy

Yang

Allen

Ding

et al. 2007

Cell. Mol. Life Sci.

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Giant axonal neuropathy (GAN) is a rare autosomal recessive disorder affecting both the central and peripheral nervous systems. Cytopathologically, the disorder is characterized by giant axons with derangements of cytoskeletal components. Geneticists refined the chromosomal interval containing the locus, culminating in the cloning of the defective gene, GAN. To date, many distinct mutations scattered throughout the coding region of the locus have been reported by researchers from different groups around the world. GAN encodes the protein, gigaxonin. Recently, a genetic mouse model of the disease was generated by targeted disruption of the locus. Over the years, the molecular mechanisms underlying GAN have attracted much interest. Studies have revealed that gigaxonin appears to play an important role in cytoskeletal functions and dynamics by directing ubiquitin-mediated degradations of cytoskeletal proteins. Aberrant accumulations of cytoskeletal-associated proteins caused by a defect in the ubiquitin-proteasome system (UPS) have been shown to be responsible for neurodegeneration occurring in GAN-null neurons, providing strong support for the notion that UPS plays crucial roles in cytoskeletal functions and dynamics. However, many key questions about the disease remain unanswered.

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“…Abnormalities are also seen in other IFs and outside the nervous system (26,28,29). Within the CNS, Rosenthal fibers have been described in several patients with GAN (25,27,30). It is intriguing to speculate that loss of gigaxonin affects GFAP, causing it to accumulate and aggregate in a manner similar to its effects on other IFs, and may even produce Alexander disease-like pathology.…”

Section: Gfap and Potential Links To Gigaxonin?mentioning

confidence: 99%

Dysfunctions of neuronal and glial intermediate filaments in disease

Liem

Messing²

2009

J. Clin. Invest.

125

100

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Intermediate filaments (IFs) are abundant structures found in most eukaryotic cells, including those in the nervous system. In the CNS, the primary components of neuronal IFs are α-internexin and the neurofilament triplet proteins. In the peripheral nervous system, a fifth neuronal IF protein known as peripherin is also present. IFs in astrocytes are primarily composed of glial fibrillary acidic protein (GFAP), although vimentin is also expressed in immature astrocytes and some mature astrocytes. In this Review, we focus on the IFs of glial cells (primarily GFAP) and neurons as well as their relationship to different neurodegenerative diseases.

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Giant Axonal Neuropathy: Clinical, Electrophysiologic, and Neuropathologic Features in Two Siblings

Cited by 31 publications

References 24 publications

Sensory-motor deficits and neurofilament disorganization in gigaxonin-null mice

Sensory-motor deficits and neurofilament disorganization in gigaxonin-null mice

Giant axonal neuropathy

Dysfunctions of neuronal and glial intermediate filaments in disease

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