Characterization of novel dystonia musculorum mutant mice: Implications for central nervous system abnormality

Horie, Minoru; Mekada, Kazuyuki; Sano, Hiromi; Kikkawa, Yoshiaki; Chiken, Satomi; Someya, Takuro; Saito, Keisuke; Hossain, M. Ibrahim; Nameta, Masaaki; Abe, Kuniya; Sakimura, Kenji; Ono, Katsuhiko; Nambu, Atsushi; Yoshiki, Atsushi; Takebayashi, Hirohide

doi:10.1016/j.nbd.2016.09.016

Cited by 17 publications

(30 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The rotarod test was conducted using an accelerating rotarod apparatus (UGO Basile, Comerio‐Varese, Italy), as previously described (Horie et al . ). Mice ( n = 10 animals per group) were placed on a rotating drum, and the latency to fall was recorded with a 300 s cutoff.…”

Section: Methodsmentioning

confidence: 97%

“…Immunohistochemistry (IHC) was performed on paraffin sections as previously described (Horie et al . ). Briefly, deparaffinized sections were immersed in 10 mM citrate buffer, pH6.0, boiled in a microwave oven for 5 min and then cooled to 20°C.…”

Section: Methodsmentioning

confidence: 97%

“…In situ hybridization (ISH) was performed on paraffin sections as previously described (Horie et al . ; Takebayashi et al . ).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Deletion of exons encoding carboxypeptidase domain of Nna1 results in Purkinje cell degeneration (pcd) phenotype

Zhou

Hossain

Yamazaki

et al. 2018

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

Purkinje cell degeneration (pcd) was first identified in a spontaneous mouse mutant showing cerebellar ataxia. In addition to cerebellar Purkinje cells (PCs), retinal photoreceptors, mitral cells in the olfactory bulb, and a discrete subpopulation of thalamic neurons also degenerate in the mutant brains. The gene responsible for the pcd mutant is Nna1, also known as ATP/GTP binding protein 1 or cytosolic carboxypeptidase-like 1, which encodes a zinc carboxypeptidase protein. To investigate pathogenesis of the pcd mutation in detail, we generated a conditional Nna1 allele targeting the carboxypeptidase domain at C-terminus. After Cre recombination and heterozygous crossing, we generated Nna1 knockout (KO) mice and found that the Nna1 KO mice began to show cerebellar ataxia at postnatal day 20 (P20). Most PCs degenerated until 4-week-old, except lobule X. Activated microglia and astrocytes were also observed in the Nna1 KO cerebellum. In the mutant brain, the Nna1 mRNA level was dramatically reduced, suggesting that nonsense-mediated mRNA decay occurs in it. Since the Nna1 protein acts as a de-glutamatase on the C-terminus of α-tubulin and β-tubulin, increased polyglutamylated tubulin was detected in the Nna1 KO cerebellum. In addition, the endoplasmic reticulum stress marker, C/EBP homologous protein (CHOP), was up-regulated in the mutant PCs. We report the generation of a functional Nna1 conditional allele and possible mechanisms of PC death in the Nna1 KO in the cerebellum. OPEN PRACTICES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

show abstract

Section: Methodsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 97%

See 1 more Smart Citation

Deletion of exons encoding carboxypeptidase domain of Nna1 results in Purkinje cell degeneration (pcd) phenotype

Zhou

Hossain

Yamazaki

et al. 2018

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Therefore, the studied hypomorphic allele of dt caused histological disturbances in the central nervous system. It was suggested that the described spontaneously emerging mutant can become a good model of hereditary sensory and vegetative neuropathy type 6, which is caused by mutations in the human DST gene …”

Section: Dystoniamentioning

confidence: 99%

“…It was suggested that the described spontaneously emerging mutant can become a good model of hereditary sensory and vegetative neuropathy type 6, which is caused by mutations in the human DST gene. 67,68 Autopsy studies of the brains from dystonia patients carried out using traditional histopathological methods revealed some structural abnormalities. These observations were combined with the results of studying the brain tissues of DYT1 mouse models of dystonia.…”

Section: Dystoniamentioning

confidence: 99%

Modern approaches for modelling dystonia and Huntington's disease in vitro and in vivo

Жунина

Yabbarov

Orekhov

et al. 2019

Int J Experimental Path

View full text Add to dashboard Cite

Summary Dystonia associated with Huntington's disease, Parkinson's disease or other neurodegenerative diseases substantially affects patients’ quality of life and is a major health problem worldwide. The above‐mentioned diseases are characterized by neurodegeneration accompanied by motor and cognitive impairment and often have complex aetiology. A frequent feature of these conditions is the abnormal accumulation of protein aggregates within specific neuronal populations in the affected brain regions. Familial neurodegenerative diseases are associated with a number of genetic mutations. Identification of these mutations allowed creation of modern model systems for studying neurodegeneration, either in cultured cells or in model animals. Animal models, especially mouse models, have contributed considerably to improving our understanding of the pathophysiology of neurodegenerative diseases. These models have allowed study of the pathogenic mechanisms and development of new disease‐modifying strategies and therapeutic approaches. However, due to the complex nature of these pathologies and the irreversible damage that they cause to the neural tissue, effective therapies against neurodegeneration remain to be elaborated. In this review, we provide an overview of cellular and animal models developed for studying neurodegenerative diseases, including Huntington's disease and dystonia of different origins.

show abstract

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

Horie

Yoshioka

Kusumi

et al. 2020

Glia

Self Cite

View full text Add to dashboard Cite

Dystonin (Dst) is a causative gene for Dystonia musculorum (dt) mice, which is an inherited disorder exhibiting dystonia‐like movement and ataxia with sensory degeneration. Dst is expressed in a variety of tissues, including the central nervous system and the peripheral nervous system (PNS), muscles, and skin. However, the Dst‐expressing cell type(s) for dt phenotypes have not been well characterized. To address the questions whether the disruption of Dst in Schwann cells induces movement disorders and how much impact does it have on dt phenotypes, we generated Dst conditional knockout (cKO) mice using P0‐Cre transgenic mice and Dst gene trap mice. First, we assessed the P0‐Cre transgene‐dependent Cre recombination using tdTomato reporter mice and then confirmed the preferential tdTomato expression in Schwann cells. In the Dst cKO mice, Dst mRNA expression was significantly decreased in Schwann cells, but it was intact in most of the sensory neurons in the dorsal root ganglion. Next, we analyzed the phenotype of Dst cKO mice. They exhibited a normal motor phenotype during juvenile periods, and thereafter, started exhibiting an ataxia. Behavioral tests and electrophysiological analyses demonstrated impaired motor abilities and slowed motor nerve conduction velocity in Dst cKO mice, but these mice did not manifest dystonic movements. Electron microscopic observation of the PNS of Dst cKO mice revealed significant numbers of hypomyelinated axons and numerous infiltrating macrophages engulfing myelin debris. These results indicate that Dst is important for normal PNS myelin organization and Dst disruption in Schwann cells induces late‐onset neuropathy and sensory ataxia. Main points Dystonin (Dst) disruption in Schwann cells results in late‐onset neuropathy and sensory ataxia. Dst in Schwann cells is important for normal myelin organization in the peripheral nervous system.

show abstract

Characterization of novel dystonia musculorum mutant mice: Implications for central nervous system abnormality

Cited by 17 publications

References 66 publications

Deletion of exons encoding carboxypeptidase domain of Nna1 results in Purkinje cell degeneration (pcd) phenotype

Deletion of exons encoding carboxypeptidase domain of Nna1 results in Purkinje cell degeneration (pcd) phenotype

Modern approaches for modelling dystonia and Huntington's disease in vitro and in vivo

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

Contact Info

Product

Resources

About