TorsinB overexpression prevents abnormal twisting in DYT1 dystonia mouse models

Li, Jay; Liang, Chun-Chi; Pappas, Samuel S.; Dauer, William T.

doi:10.1101/836536

Cited by 5 publications

(9 citation statements)

References 44 publications

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“…We find that torsinA activation early enough to prevent ChI degeneration rescues motor abnormalities, while torsinA activation in adult mice, after ChI degeneration is complete, does not improve the motor phenotype. These findings are consistent with another recent study demonstrating an association between ChI survival and motor symptoms (44), further strengthening the relationship between striatal cholinergic dysfunction and dystonic-like movements. However, other cells lack torsinA in Dlx-CKO mice, and selective degeneration of ChIs does not imply that they are the only key player.…”

Section: Discussionsupporting

confidence: 92%

“…Changes not amenable to torsinA repletion likely include ChI degeneration, as initiating torsinA replacement after ChI loss is ineffective. An association between prevention of ChI degeneration and behavioral rescue has been demonstrated in torsinA LOF models (44,45), further supporting this connection. Striatal dysfunction secondary to ChI loss and dysfunction likely causes additional abnormalities of connectivity and function within and beyond the striatum, and failure to restore torsinA in these other neural elements may in part account for the incomplete motor rescue we observe.…”

Section: Discussionmentioning

confidence: 52%

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TorsinA restoration in a mouse model identifies a critical therapeutic window for DYT1 dystonia

Li¹,

Levin²,

Kim³

et al. 2021

Journal of Clinical Investigation

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In inherited neurodevelopmental diseases, pathogenic processes unique to critical periods during early brain development may preclude effectiveness of gene modification therapies applied later in life. We explored this question in a mouse model of DYT1 dystonia, a neurodevelopmental disease caused by a loss-of-function mutation in the TOR1A gene encoding torsinA. To define the temporal requirements for torsinA in normal motor function and gene replacement therapy, we developed a mouse line enabling spatiotemporal control of the endogenous torsinA allele. Suppressing torsinA during embryogenesis caused dystonia-mimicking behavioral and neuropathological phenotypes. Suppressing torsinA during adulthood, however, elicited no discernible abnormalities, establishing an essential requirement for torsinA during a developmental critical period. The developing CNS exhibited a parallel "therapeutic critical period" for torsinA repletion. While restoring torsinA in juvenile DYT1 mice rescued motor phenotypes, there was no benefit from adult torsinA repletion. These data establish a unique requirement for torsinA in the developing nervous system and demonstrate that the critical period genetic insult provokes permanent pathophysiology mechanistically delinked from torsinA function. These findings imply that to be effective, torsinA-based therapeutic strategies must be employed early in the course of DYT1 dystonia.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 52%

TorsinA restoration in a mouse model identifies a critical therapeutic window for DYT1 dystonia

Li¹,

Levin²,

Kim³

et al. 2021

Journal of Clinical Investigation

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“…Recently, in the TOR1A ‐dystonia mouse model, reduced expression of torsinB encoded by the paralog TOR1B was found to cause a dose‐dependent worsening of twisting, whereas torsinB overexpression was proven to rescue torsinA deficiency 72 . These findings identify torsinB as a potent modifier of torsinA loss‐of‐function phenotypes and suggest that enhancing neuronal torsinB expression in neurons at the appropriate developmental stage might represent a promising disease‐modifying strategy 72 …”

Section: Mechanisms Underlying Phenotypic Heterogeneitymentioning

confidence: 99%

Challenges in Clinicogenetic Correlations: One Gene – Many Phenotypes

Magrinelli

Balint

Bhatia

2021

Movement Disord Clin Pract

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Background Background: Progress in geneticsparticularly the advent of next-generation sequencing (NGS)has enabled an unparalleled gene discovery and revealed unmatched complexity of genotypephenotype correlations in movement disorders. Among other things, it has emerged that mutations in one and the same gene can cause multiple, often markedly different phenotypes. Consequently, movement disorder specialists have increasingly experienced challenges in clinicogenetic correlations. Objectives Objectives: To deconstruct biological phenomena and mechanistic bases of phenotypic heterogeneity in monogenic movement disorders and neurodegenerative diseases. To discuss the evolving role of movement disorder specialists in reshaping disease phenotypes in the NGS era. Methods Methods: This scoping review details phenomena contributing to phenotypic heterogeneity and their underlying mechanisms. Results Results: Three phenomena contribute to phenotypic heterogeneity, namely incomplete penetrance, variable expressivity and pleiotropy. Their underlying mechanisms, which are often shared across phenomena and nonmutually exclusive, are not fully elucidated. They involve genetic factors (ie, different mutation types, dynamic mutations, somatic mosaicism, intragenic intra-and inter-allelic interactions, modifiers and epistatic genes, mitochondrial heteroplasmy), epigenetic factors (ie, genomic imprinting, X-chromosome inactivation, modulation of genetic and chromosomal defects), and environmental factors. Conclusion Conclusion: Movement disorders is unique in its reliance on clinical judgment to accurately define disease phenotypes. This has been reaffirmed by the NGS revolution, which provides ever-growing sequencing data and fuels challenges in variant pathogenicity assertions for such clinically heterogeneous disorders. Deep phenotyping, with characterization and continual updating of "core" phenotypes, and comprehension of determinants of genotype-phenotype complex relationships are crucial for clinicogenetic correlations and have implications for the diagnosis, treatment and counseling. "Phenotype" is the observable or quantifiable characteristics of an individualincluding findings of nongenetic investigationswhich result from the interaction of its gene makeup with environmental factors. However, in a narrower sense, geneticists refer to phenotype as the set of specific features arising from the expression of one or few genes. In keeping with this, "genotype" is the genetic constitution of an individual, overall or at a specific locus, that is responsible of a given phenotype. 1 The identification of the first disease genes in the early 1980s suggested simplistically that phenotypes could be precisely predicted if genotypes were determined, therefore enabling consistent genotype-phenotype correlations. 2 However, advances in genetics particularly the advent of next-generation sequencing (NGS)have revealed that the relationship between genotype and phenotype is not straightforward, even for single-gene disorders. 1,2 This has...

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“…TorsinA remains the best characterized as it is the only one with a known disease-associated mutation. In mammals, TorsinA and TorsinB have a high degree of sequence similarity (~84% in humans) and at least some functional redundancy [18][19][20]. However, their expression patterns are quite different.…”

Section: Figure 2 (A)mentioning

confidence: 99%

The Role of Torsin AAA+ Proteins in Preserving Nuclear Envelope Integrity and Safeguarding Against Disease

2020

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Torsin ATPases are members of the AAA+ (ATPases associated with various cellular activities) superfamily of proteins, which participate in essential cellular processes. While AAA+ proteins are ubiquitously expressed and demonstrate distinct subcellular localizations, Torsins are the only AAA+ to reside within the nuclear envelope (NE) and endoplasmic reticulum (ER) network. Moreover, due to the absence of integral catalytic features, Torsins require the NE- and ER-specific regulatory cofactors, lamina-associated polypeptide 1 (LAP1) and luminal domain like LAP1 (LULL1), to efficiently trigger their atypical mode of ATP hydrolysis. Despite their implication in an ever-growing list of diverse processes, the specific contributions of Torsin/cofactor assemblies in maintaining normal cellular physiology remain largely enigmatic. Resolving gaps in the functional and mechanistic principles of Torsins and their cofactors are of considerable medical importance, as aberrant Torsin behavior is the principal cause of the movement disorder DYT1 early-onset dystonia. In this review, we examine recent findings regarding the phenotypic consequences of compromised Torsin and cofactor activities. In particular, we focus on the molecular features underlying NE defects and the contributions of Torsins to nuclear pore complex biogenesis, as well as the growing implications of Torsins in cellular lipid metabolism. Additionally, we discuss how understanding Torsins may facilitate the study of essential but poorly understood processes at the NE and ER, and aid in the development of therapeutic strategies for dystonia.

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TorsinB overexpression prevents abnormal twisting in DYT1 dystonia mouse models

Cited by 5 publications

References 44 publications

TorsinA restoration in a mouse model identifies a critical therapeutic window for DYT1 dystonia

TorsinA restoration in a mouse model identifies a critical therapeutic window for DYT1 dystonia

Challenges in Clinicogenetic Correlations: One Gene – Many Phenotypes

The Role of Torsin AAA+ Proteins in Preserving Nuclear Envelope Integrity and Safeguarding Against Disease

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