Emerging common molecular pathways for primary dystonia

LeDoux, Mark S.; Dauer, William T.; Warner, Thomas T.

doi:10.1002/mds.25547

Cited by 40 publications

(48 citation statements)

References 133 publications

(251 reference statements)

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“…13 For example, mutations in TOR1A and GNAL both disturb dopamine signaling, which is consistent with other lines of evidence suggesting a role for abnormal dopamine function in dystonia. TOR1A, THAP1, and CIZ1 have been shown to be involved in cell cycle control and transcriptional regulation, highlighting that defects in these critical cellular functions could play a key role.…”

supporting

confidence: 87%

Dystonia

Berman

Jinnah

2015

Neur Clin Pract

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SummaryThere has been considerable progress in our understanding of dystonia over the last century. Growing recognition of dystonia has enhanced awareness of its diverse motor phenomenology and brought attention to the importance that nonmotor features may play in this disorder, once considered to be purely motor. Using the latest technologies in human genetics, new genetic links are being discovered at an ever-quickening pace and expanding our knowledge of the disorder's complex pathogenesis. Furthermore, as we gain clearer insight into the pathophysiology of dystonia and an appreciation of the involvement of dysfunction outside the basal ganglia, dystonia has been increasingly viewed as a network disorder. Here we briefly discuss some of the recent noteworthy advances.

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supporting

confidence: 87%

Dystonia

Berman

Jinnah

2015

Neur Clin Pract

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“…However, we cannot exclude the possibility that some of these changes in gene expression were not due to novel effects of mutant ε-SG/β-gal fusion protein(s) that resulted from insertion of the Gep-SD5 gene-trap vector into intron 9 of Sgce . Although a single-pass transmembrane cell-surface protein seemingly involved in synaptic transmission, our gene expression data suggests that ε-SG shows functional overlap with other dystonia proteins such as TAF1, CIZ1, torsinA, THAP1, and Gα(olf) which play direct or indirect roles in cell cycle control, DNA repair and neurodevelopment (LeDoux et al, 2013, Xiao et al, 2016). …”

Section: Discussionmentioning

confidence: 89%

“…Intermittent subclinical involuntary movements and/or anxiety could be responsible for differential up-regulation of the immediate-early genes Fos , Nr4a3, Nr4a2 , and Nr4a1 in Sgce m+/pGt mice (Huguet et al, 2016). CDKN1A is an essential cell-cycle protein that interacts with the dystonia-associated protein CIZ1 (LeDoux et al, 2013, Xiao et al, 2012) and CD55 regulates the complement system, an important player in neuronal differentiation (Stephan et al, 2012). Snord35a , Snora35 and Snord14e encode small nucleolar RNAs, a class of RNA molecules that contribute to modifications of rRNA and tRNAs such as methylation and pseudouridylation.…”

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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“…In spite of these apparent discrepancies, that may be attributed to different experimental factors, but also to the intrinsic nature of a very heterogeneous disorder (Breakefield et al, 2008; Tanabe et al, 2009), the electrophysiological phenotype appears to be constantly reproducible across different mouse lines as well as in rat. Indeed, they produced convergent evidence suggesting common pathogenic features in dystonia (Ledoux et al, 2013), such as the involvement of basal ganglia and the prominent role of dopamine signaling (Augood et al, 2004; Perlmutter and Mink, 2004; Pisani et al, 2006; Wichmann, 2008; Zhao et al, 2008; Bragg et al, 2011; Albanese and Lalli, 2012; Goodchild et al, 2013). …”

Section: Cholinergic Function In Animal Models Of Dystoniamentioning

confidence: 99%

Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia

Jaunarajs

Bonsi

Chesselet

et al. 2015

Progress in Neurobiology

149

119

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Dystonia is a movement disorder of both genetic and non-genetic causes, which typically results in twisted posturing due to abnormal muscle contraction. Evidence from dystonia patients and animal models of dystonia indicate a crucial role for the striatal cholinergic system in the pathophysiology of dystonia. In this review, we focus on striatal circuitry and the centrality of the acetylcholine system in the function of the basal ganglia in the control of voluntary movement and ultimately clinical manifestion of movement disorders. We consider the impact of cholinergic interneurons (ChIs) on dopamine-acetylcholine interactions and examine new evidence for impairment of ChIs in dysfunction of the motor systems producing dystonic movements, particularly in animal models. We have observed paradoxical excitation of ChIs in the presence of dopamine D2 receptor agonists and impairment of striatal synaptic plasticity in a mouse model of DYT1 dystonia, which are improved by administration of recently developed M1 receptor antagonists. These findings have been confirmed across multiple animal models of DYT1 dystonia and may represent a common endophenotype by which to investigate dystonia induced by other types of genetic and non-genetic causes and to investigate the potential effectiveness of pharmacotherapeutics and other strategies to improve dystonia.

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Emerging common molecular pathways for primary dystonia

Cited by 40 publications

References 133 publications

Dystonia

Dystonia

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

Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia

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