Earlier onset of motor deficits in mice with double mutations in Dyt1 and Sgce

Yokoi, Fumiaki; Yang, Guang; Li, JinDong; DeAndrade, Mark P.; Zhou, Tong; Li, Yuqing

doi:10.1093/jb/mvq078

Cited by 40 publications

(54 citation statements)

References 43 publications

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“…All Sgce models have shown impaired performance on the raised-beam task with increased numbers of slips (Yokoi et al, 2006, Yokoi et al, 2012a, Yokoi et al, 2012b, Yokoi et al, 2010). Sgce null mice had increased vertical open-field motor activity, anxiety-like behavior, myoclonus and increased striatal dopamine (Yokoi et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Role of major and brain-specific Sgce isoforms in the pathogenesis of myoclonus-dystonia syndrome

Xiao

Vemula

Xue

et al. 2017

Neurobiology of Disease

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Loss-of-function mutations in SGCE, which encodes ε-sarcoglycan (ε-SG), cause myoclonus--dystonia syndrome (OMIM159900, DYT11). A “major” ε-SG protein derived from CCDS5637.1 (NM_003919.2) and a “brain-specific” protein, that includes sequence derived from alternative exon 11b (CCDS47642.1, NM_001099400.1), are reportedly localized in post- and pre-synaptic membrane fractions, respectively. Moreover, deficiency of the “brain-specific” isoform and other isoforms derived from exon 11b may be central to the pathogenesis of DYT11. However, no animal model supports this hypothesis. Gene-trapped ES cells (CMHD-GT_148G1-3, intron 9 of NM_011360) were used to generate a novel Sgce mouse model (C57BL/6J background) with markedly reduced expression of isoforms derived from exons 3′ to exon 9 of NM_011360. Among those brain regions analyzed in adult (2 month-old) wild-type (WT) mice, cerebellum showed the highest relative expression of isoforms incorporating exon 11b. Homozygotes (SgceGt(148G1)Cmhd/Gt(148G1)Cmhd or SgceGt/Gt) and paternal heterozygotes (Sgcem+/pGt, m-maternal, p-paternal) showed 60 to 70% reductions in expression of total Sgce. Although expression of the major (NM_011360) and brain-specific (NM_001130189) isoforms was markedly reduced, expression of short isoforms was preserved and relatively small amounts of chimeric ε-SG/β-galactosidase fusion protein was produced by the Sgce gene-trap locus. Immunoaffinity purification followed by mass spectrometry assessments of Sgcem+/pGt mouse brain using pan- or brain-specific ε-SG antibodies revealed significant reductions of ε-SG and other interacting sarcoglycans. Genome-wide gene-expression data using RNA derived from adult Sgcem+/pGt mouse cerebellum showed that the top up-regulated genes were involved in cell cycle, cellular development, cell death and survival, while the top down-regulated genes were associated with protein synthesis, cellular development, and cell death and survival. In comparison to WT littermates, Sgcem+/pGt mice exhibited “tiptoe” gait and stimulus-induced appendicular posturing between Postnatal Days 14 to 16. Abnormalities noted in older Sgcem+/pGt mice included reduced body weight, altered gait dynamics, and reduced open-field activity. Overt spontaneous or stimulus-sensitive myoclonus was not apparent on the C57BL/6J background or mixed C57BL/6J-BALB/c and C57BL/6J-129S2 backgrounds. Our data confirm that mouse Sgce is a maternally imprinted gene and suggests that short Sgce isoforms may compensate, in part, for deficiency of major and brain-specific Sgce isoforms.

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Section: Discussionmentioning

confidence: 99%

Role of major and brain-specific Sgce isoforms in the pathogenesis of myoclonus-dystonia syndrome

Xiao

Vemula

Xue

et al. 2017

Neurobiology of Disease

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“…These results suggest that decreased D1R and D2R may be caused by translational or post-translational processes, such as modification, assembly, trafficking or stabilization. Since the torsinA level is reduced in Dyt1 KI mouse brains [36, 51–53], partial loss of torsinA function may cause trafficking deficits of striatal D1R and D2R and affect their stability. Other studies have shown that torsinA possesses molecular chaperon-like activities [8–10], the partial loss of molecular chaperon-like activity of torsinA may be responsible for D1R reduction at the posttranslational steps.…”

Section: Discussionmentioning

confidence: 99%

“…The striatal proteins were also extracted from other six to twelve of Dyt1 ΔGAG heterozygous KI and their WT littermate mice in the RIPA buffer or 1% Triton X100 as previously described [36]. The proteins were separated on SDS-PAGE gels and transferred to PROTRAN nitrocellulose transfer membranes (Whatman).…”

Section: Methodsmentioning

confidence: 99%

Decreased dopamine receptor 1 activity and impaired motor-skill transfer in Dyt1 ΔGAG heterozygous knock-in mice

Yokoi

Dang

et al. 2015

Behavioural Brain Research

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DYT1 dystonia is a movement disorder caused by a trinucleotide deletion (ΔGAG) in DYT1 (TOR1A), corresponding to a glutamic acid loss in the C-terminal region of torsinA. Functional alterations in the basal ganglia circuits have been reported in both DYT1 dystonia patients and rodent models. Dyt1 ΔGAG heterozygous knock-in (KI) mice exhibit motor deficits and decreased striatal dopamine receptor 2 (D2R) binding activity, suggesting a malfunction of the indirect pathway. However, the role of the direct pathway in pathogenesis of dystonia is not yet clear. Here, we report that Dyt1 KI mice exhibit significantly decreased striatal dopamine receptor 1 (D1R) binding activity and D1R protein levels, suggesting the alteration of the direct pathway. The decreased D1R may be caused by translational or post-translational processes since Dyt1 KI mice had normal levels of striatal D1R mRNA and a normal number of striatal neurons expressing D1R. Levels of striatal ionotropic glutamate receptor subunits, dopamine transporter, acetylcholine muscarinic M4 receptor and adenosine A2A receptor were not altered suggesting a specificity of affected polytopic membrane-associated proteins. Contribution of the direct pathway to motor-skill learning has been suggested in another pharmacological rat model injected with a D1R antagonist. In the present study, we developed a novel motor skill transfer test for mice and found deficits in Dyt1 KI mice. Further characterization of both the direct and the indirect pathways in Dyt1 KI mice will aid the development of novel therapeutic drugs.

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“…Therefore, it can be speculated that loss or reduction of the torsin A function (e.g., occurring in DYT1 dystonia) may affect the quality control of SGCE and alter the amount of SGCE in vitro . Moreover, an animal experiment has demonstrated simultaneous mutations in two dystonia genes (DYT1 and DYT11) facilitate the onset of motor deficits in mice, suggesting that the additional multiple mutations are risk factors of early onset in this disease39. Further research on MDS patients with double mutations may provide clinical insight on this issue.…”

Section: Discussionmentioning

confidence: 99%

Deep brain stimulation for myoclonus-dystonia syndrome with double mutations in DYT1 and DYT11

Wang

et al. 2017

Sci Rep

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Myoclonus-dystonia syndrome (MDS) is a rare autosomal dominant inherited disorder characterized by the presentation of both myoclonic jerks and dystonia. Evidence is emerging that deep brain stimulation (DBS) may be a promising treatment for MDS. However, there are no studies reporting the effects of DBS on MDS with double mutations in DYT1 and DYT11. Two refractory MDS patients with double mutations were treated between 2011 and 2015 in our center. Genetic testing for DYT1 and DYT11 was performed through polymerase chain reaction amplification and direct sequencing of the specific exons of genes. For the first patient, initial bilateral ventral intermediate thalamus nucleus (Vim) DBS was performed. Because of worsening dystonia after initial improvement in symptoms, subsequent bilateral globus pallidus internus (GPi) DBS was offered at 43 months after initial surgery, which reversed the deterioration and restored the motor function. For the second patient, initial improvement in motor symptoms and quality of life was sustained at the follow-up 6 months after bilateral Vim DBS treatment. Thus, DBS may be an effective therapeutic option for MDS, even in patients with double mutations. Moreover, GPi DBS may be used as a supplementary treatment when initial Vim DBS fails to control MDS symptoms.

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Earlier onset of motor deficits in mice with double mutations in Dyt1 and Sgce

Cited by 40 publications

References 43 publications

Role of major and brain-specific Sgce isoforms in the pathogenesis of myoclonus-dystonia syndrome

Role of major and brain-specific Sgce isoforms in the pathogenesis of myoclonus-dystonia syndrome

Decreased dopamine receptor 1 activity and impaired motor-skill transfer in Dyt1 ΔGAG heterozygous knock-in mice

Deep brain stimulation for myoclonus-dystonia syndrome with double mutations in DYT1 and DYT11

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