Disruption of <scp><i>dystonin</i></scp> in Schwann cells results in late‐onset neuropathy and sensory ataxia

Horie, Minoru; Yoshioka, Nozomu; Kusumi, Satoshi; Sano, Hiromi; Kurose, Masayuki; Watanabe-Iida, Izumi; Hossain, M. Ibrahim; Chiken, Satomi; Abe, Manabu; Yamamura, Kensuke; Sakimura, Kenji; Nambu, Atsushi; Shibata, Masahiro; Takebayashi, Hirohide

doi:10.1002/glia.23843

Cited by 7 publications

(6 citation statements)

References 56 publications

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“…Conditional deletion of Plec from epidermal cells causes epidermal barrier defects and skin blistering ( Ackerl et al, 2007 ), both of which is more severe than that observed in dt mice carrying Dst-e mutations ( Guo et al, 1995 ; Yoshioka et al, 2020 ). Furthermore, we recently demonstrated that conditional deletion of Dst from Schwann cells in the peripheral nervous system leads to disorganization of the myelin sheath ( Horie et al, 2020 ), similar to that observed for Plec -deficient Schwann cells ( Walko et al, 2013 ). These studies suggest that Dst and plectin, which are plakin family proteins, have overlapping roles in different cell types.…”

Section: Discussionmentioning

confidence: 62%

“…Some Dst-b E2610Ter/E2610Ter mice exhibited kyphosis (data not shown). We have reported that dt mice display impairment of motor coordination as assessed by the rotarod test and wire hang test ( Horie et al, 2020 ); however, WT and Dst-b E2610Ter/E2610Ter mice older than 1 year exhibited normal motor coordination ( Figure 2I ). These data also support the idea that deficiency of the Dst-a isoform, but not the Dst-b isoform, is causative of dt phenotypes, including sensory neuron degeneration, abnormal movements, and postnatal lethality.…”

Section: Resultsmentioning

confidence: 99%

“…The rotarod test and wire hang test (O’Hara & Co., Tokyo, Japan) were performed to evaluate motor coordination as described in the previous study with slight modification ( Horie et al, 2020 ). In the rotarod test, the latency to fall from a rotating rod (30 mm diameter) with an acceleration from 10 to 150 rpm was measured.…”

Section: Methodsmentioning

confidence: 99%

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Isoform-specific mutation in Dystonin-b gene causes late-onset protein aggregate myopathy and cardiomyopathy

Yoshioka

Kurose

Yano

et al. 2022

eLife

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Dystonin (DST), which encodes cytoskeletal linker proteins, expresses three tissue-selective isoforms: neural DST-a, muscular DST-b, and epithelial DST-e. DST mutations cause different disorders, including hereditary sensory and autonomic neuropathy 6 (HSAN-VI) and epidermolysis bullosa simplex; however, etiology of the muscle phenotype in DST-related diseases has been unclear. Because DST-b contains all of the DST-a-encoding exons, known HSAN-VI mutations could affect both DST-a and DST-b isoforms. To investigate the specific function of DST-b in striated muscles, we generated a Dst-b-specific mutant mouse model harboring a nonsense mutation. Dst-b mutant mice exhibited late-onset protein aggregate myopathy and cardiomyopathy without neuropathy. We observed desmin aggregation, focal myofibrillar dissolution, and mitochondrial accumulation in striated muscles, which are common characteristics of myofibrillar myopathy. We also found nuclear inclusions containing p62, ubiquitin, and SUMO proteins with nuclear envelope invaginations as a unique pathological hallmark in Dst-b mutation-induced cardiomyopathy. RNA-sequencing analysis revealed changes in expression of genes responsible for cardiovascular functions. In silico analysis identified DST-b alleles with nonsense mutations in populations worldwide, suggesting that some unidentified hereditary myopathy and cardiomyopathy are caused by DST-b mutations. Here, we demonstrate that the Dst-b isoform is essential for long-term maintenance of striated muscles.

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Section: Discussionmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 99%

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Isoform-specific mutation in Dystonin-b gene causes late-onset protein aggregate myopathy and cardiomyopathy

Yoshioka

Kurose

Yano

et al. 2022

eLife

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“…This difference is probably due to differential recombination in Schwann cells. We have previously demonstrated the significance of Dst in Schwann cells for maintaining myelin sheaths in the PNS ( 43 ). Conditional Dst deletion in Schwann cells using a P0-Cre transgene resulted in late-onset neuropathy with prolongation of M response latency.…”

Section: Discussionmentioning

confidence: 99%

Sensory-motor circuit is a therapeutic target for dystonia musculorum mice, a model of hereditary sensory and autonomic neuropathy 6

Yoshioka,

Kurose,

Sano

et al. 2024

Sci. Adv.

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Mutations in Dystonin ( DST ), which encodes cytoskeletal linker proteins, cause hereditary sensory and autonomic neuropathy 6 (HSAN-VI) in humans and the dystonia musculorum ( dt ) phenotype in mice; however, the neuronal circuit underlying the HSAN-VI and dt phenotype is unresolved. dt mice exhibit dystonic movements accompanied by the simultaneous contraction of agonist and antagonist muscles and postnatal lethality. Here, we identified the sensory-motor circuit as a major causative neural circuit using a gene trap system that enables neural circuit-selective inactivation and restoration of Dst by Cre-mediated recombination. Sensory neuron–selective Dst deletion led to motor impairment, degeneration of proprioceptive sensory neurons, and disruption of the sensory-motor circuit. Restoration of Dst expression in sensory neurons using Cre driver mice or a single postnatal injection of Cre-expressing adeno-associated virus ameliorated sensory degeneration and improved abnormal movements. These findings demonstrate that the sensory-motor circuit is involved in the movement disorders in dt mice and that the sensory circuit is a therapeutic target for HSAN-VI.

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“…Immunohistochemistry (IHC) on paraffin sections was performed as previously described (Horie et al, 2020; Takebayashi et al, 2000). Paraffin sections were deparaffinized with xylene, rehydrated through a descending ethanol series, and immersed in distilled water.…”

Section: Methodsmentioning

confidence: 99%

Ddx20, DEAD box helicase 20, is essential for the differentiation of oligodendrocyte and maintenance of myelin gene expression

Simankova

Bizen

Saitoh

et al. 2021

Glia

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Oligodendrocytes form myelin sheaths that surround axons, contributing to saltatory conduction and proper central nervous system (CNS) function. Oligodendrocyte progenitor cells (OPCs) are generated during the embryonic stage and differentiate into myelinating oligodendrocytes postnatally. Ddx20 is a multifunctional, DEAD-box helicase involved in multiple cellular processes, including transcription, splicing, micro-RNA biogenesis, and translation. Although defects in each of these processes result in abnormal oligodendrocyte differentiation and myelination, the involvement of Ddx20 in oligodendrocyte terminal differentiation remains unknown. To address this question, we used Mbp-Cre mice to generate Ddx20 conditional knockout (cKO) mice to allow for the deletion of Ddx20 from mature oligodendrocytes. Mbp-Cre;Ddx20 cKO mice demonstrated small body sizes, behavioral abnormalities, muscle weakness, and short lifespans, with mortality by the age of 2 months old. Histological analyses demonstrated significant reductions in the number of mature oligodendrocytes and drastic reductions in the expression levels of myelin-associated mRNAs, such as Mbp and Plp at postnatal day 42. The number of OPCs did not change. A thin myelin layer was observed for large-diameter axons in Ddx20 cKO mice, based on electron microscopic analysis. A bromodeoxyuridine (BrdU) labeling experiment demonstrated that terminal differentiation was perturbed from ages 2 weeks to 7 weeks in the CNS of Mbp-Cre;Ddx20 cKO mice. The activation of mitogen-activated protein (MAP) kinase, which promotes myelination, was downregulated in the Ddx20 cKO mice based on immunohistochemical detection. These results indicate that Ddx20 is an essential factor for terminal differentiation of oligodendrocytes and maintenance of myelin gene expression.

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Disruption of dystonin in Schwann cells results in late‐onset neuropathy and sensory ataxia

Cited by 7 publications

References 56 publications

Isoform-specific mutation in Dystonin-b gene causes late-onset protein aggregate myopathy and cardiomyopathy

Isoform-specific mutation in Dystonin-b gene causes late-onset protein aggregate myopathy and cardiomyopathy

Sensory-motor circuit is a therapeutic target for dystonia musculorum mice, a model of hereditary sensory and autonomic neuropathy 6

Ddx20, DEAD box helicase 20, is essential for the differentiation of oligodendrocyte and maintenance of myelin gene expression

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