Down‐regulation of <i>torp4a</i>, encoding the <i>Drosophila</i> homologue of torsinA, results in increased neuronal degeneration

Muraro, Nara I.; Moffat, K.

doi:10.1002/neu.20313

Cited by 38 publications

(29 citation statements)

References 64 publications

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“…5). Thus, these results support the earlier identification of Punch, as a dtorsininteracting gene [87]. Subsequent interaction experiments demonstrated that torsin -/+ ; ple -/+ mutants, doubly heterozygous for dtorsin and tyrosine hydroxylase, respectively, displayed a mildly enhanced locomotion phenotype, while heterozygous Punch mutations strongly enhanced mobility deficits in combination with the heterozygous torsin knock-out mutation.…”

Section: Drosophila Models Of Dyt1 Dystoniasupporting

confidence: 74%

“…Further analysis revealed that dopaminergic neurons were present in mutant brains and expressed tyrosine hydroxylase, the first and rate-limiting enzyme in dopamine biosynthesis. Thus, unlike RNAi knock-down of dtorsin in the fly eye [87], neural degeneration in torsin-deficient CNS was not evident. Nevertheless, DA pools in hemizygous males and heterozygous females were strongly reduced, which could be due to diminished synthesis of, or increased turnover of, this catecholamine.…”

Section: Drosophila Models Of Dyt1 Dystoniamentioning

confidence: 99%

“…The torsin/torp4a gene in Drosophila encodes a product that is 34% identical to torsinA and of similar size ( Table 1). Initially, in the absence of mutant alleles of this gene, RNAi knockdown and over-expression of the wild type gene were used to assess the cellular functions of this torsin ortholog [87]. Expression was targeted to the Drosophila retina with the eye-specific GAL4 driver, gmrGal4.…”

Section: Drosophila Models Of Dyt1 Dystoniamentioning

confidence: 99%

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Invertebrate Models of Dystonia

Caldwell¹,

Shu²,

Roberts³

et al. 2013

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Abstract:The neurological movement disorder dystonia is an umbrella term for a heterogeneous group of related conditions where at least 20 monogenic forms have been identified. Despite the substantial advances resulting from the identification of these loci, the function of many DYT gene products remains unclear. Comparative genomics using simple animal models to examine the evolutionarily conserved functional relationships with monogenic dystonias represents a rapid route toward a comprehensive understanding of these movement disorders. Current studies using the invertebrate animal models Caenorhabditis elegans and Drosophila melanogaster are uncovering cellular functions and mechanisms associated with mutant forms of the well-conserved gene products corresponding to DYT1, DYT5a, DYT5b, and DYT12 dystonias. Here we review recent findings from the invertebrate literature pertaining to molecular mechanisms of these gene products, torsinA, GTP cyclohydrolase I, tyrosine hydroxylase, and the alpha subunit of Na+/K ATPase, respectively. In each study, the application of powerful genetic tools developed over decades of intensive work with both of these invertebrate systems has led to mechanistic insights into these human disorders. These models are particularly amenable to large-scale genetic screens for modifiers or additional alleles, which are bolstering our understanding of the molecular functions associated with these gene products. Moreover, the use of invertebrate models for the evaluation of DYT genetic loci and their genetic interaction networks has predictive value and can provide a path forward for therapeutic intervention.

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Section: Drosophila Models Of Dyt1 Dystoniasupporting

confidence: 74%

Section: Drosophila Models Of Dyt1 Dystoniamentioning

confidence: 99%

Section: Drosophila Models Of Dyt1 Dystoniamentioning

confidence: 99%

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Invertebrate Models of Dystonia

Caldwell¹,

Shu²,

Roberts³

et al. 2013

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“…One hypothesis is that torsinA may have a chaperone-like function (44,45), regulating the folding of proteins involved in SV trafficking, such us snapin. Interestingly, torsinA displays sequence homology with N-ethylmaleimide-sensitive fusion protein (5), an AAA-ATPase essential for neurosecretion that is responsible for SNARE recycling (46).…”

Section: Discussionmentioning

confidence: 99%

The Dystonia-associated Protein TorsinA Modulates Synaptic Vesicle Recycling

Granata

Watson

Collinson

et al. 2008

Journal of Biological Chemistry

105

108

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The loss of a glutamic acid residue in the AAA-ATPase (ATPases associated with diverse cellular activities) torsinA is responsible for most cases of early onset autosomal dominant primary dystonia. In this study, we found that snapin, which binds SNAP-25 (synaptosome-associated protein of 25,000 Da) and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild type and mutant torsinA. Snapin co-localized with endogenous torsinA on dense core granules in PC12 cells and was recruited to perinuclear inclusions containing mutant ⌬E-torsinA in neuroblastoma SH-SY5Y cells. In view of these observations, synaptic vesicle recycling was analyzed using the lipophilic dye FM1-43 and an antibody directed against an intravesicular epitope of synaptotagmin I. We found that overexpression of wild type torsinA negatively affects synaptic vesicle endocytosis. Conversely, overexpression of ⌬E-torsinA in neuroblastoma cells increases FM1-43 uptake. Knockdown of snapin and/or torsinA using small interfering RNAs had a similar inhibitory effect on the exo-endocytic process. In addition, down-regulation of torsinA causes the persistence of synaptotagmin I on the plasma membrane, which closely resembles the effect observed by the overexpression of the ⌬E-torsinA mutant. Altogether, these findings suggest that torsinA plays a role together with snapin in regulated exocytosis and that ⌬E-torsinA exerts its pathological effects through a loss of function mechanism. This may affect neuronal uptake of neurotransmitters, such as dopamine, playing a role in the development of dystonic movements.The majority of cases of early onset, primary torsion dystonia are caused by a dominantly inherited mutation in the DYT1 (TOR1A) gene on chromosome 9q34 (1). DYT1 dystonia manifests in childhood, typically with dystonia in a limb that spreads to the trunk and other limbs, usually sparing cranio-cervical muscles (2, 3). There is no evidence for neurodegeneration in DYT1 dystonia, implying that abnormal movements are caused by a functional neuronal defect (4). All cases of typical DYT1 dystonia are caused by an in-frame GAG deletion (⌬GAG302/ 303; ⌬E) in DYT1 gene, resulting in the loss of a glutamic acid in the C-terminal region of the encoded protein, torsinA (1).TorsinA is a member of the AAA ATPase superfamily of chaperone-like proteins (5). In mammalian neuronal cells, torsinA is found throughout the cytoplasm, neurite processes, and growth cones (6, 7). TorsinA has also been found in the lumen of the endoplasmic reticulum (ER) 3 and in the space between the inner and the outer membrane of the nuclear envelope (NE) (8 -11). In contrast, in cells overexpressing the mutant (⌬E-torsinA), the protein is redistributed from ER to NE and accumulates in large perinuclear membranous inclusions, which appeared to arise from the nuclear envelope (7,(12)(13)(14). TorsinA-positive inclusions have been found in the midbrain of DYT1 patients, suggesting that they are relevant to the pathogenesis of DYT1 dystonia (15...

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“…Indeed, a neuroprotective role for torsins is further suggested by a report in flies, where targeted RNAi knockdown of torp4a, the only Drosophila torsinA homolog, causes progressive retinal degeneration (Muraro and Moffat, 2006). In this regard, the enhancement of native WT torsinA function may not only serve to overcome the neuronal deficit of mutant torsinA-associated EOTD, but might also be of benefit to the treatment of diseases resulting from defects in processing mutant proteins (e.g.…”

Section: Discussionmentioning

confidence: 99%

Chemical enhancement of torsinA function in cell and animal models of torsion dystonia

Cao

Hewett

Yokoi³

et al. 2010

Disease Models &Amp; Mechanisms

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SUMMARYMovement disorders represent a significant societal burden for which therapeutic options are limited and focused on treating disease symptomality. Early-onset torsion dystonia (EOTD) is one such disorder characterized by sustained and involuntary muscle contractions that frequently cause repetitive movements or abnormal postures. Transmitted in an autosomal dominant manner with reduced penetrance, EOTD is caused in most cases by the deletion of a glutamic acid (DE) in the DYT1 (also known as TOR1A) gene product, torsinA. Although some patients respond well to anticholingerics, therapy is primarily limited to either neurosurgery or chemodenervation. As mutant torsinA (DE) expression results in decreased torsinA function, therapeutic strategies directed toward enhancement of wild-type (WT) torsinA activity in patients who are heterozygous for mutant DYT1 may restore normal cellular functionality. Here, we report results from the first-ever screen for candidate small molecule therapeutics for EOTD, using multiple activity-based readouts for torsinA function in Caenorhabditis elegans, subsequent validation in human DYT1 patient fibroblasts, and behavioral rescue in a mouse model of DYT1 dystonia. We exploited the nematode to rapidly discern chemical effectors of torsinA and identified two classes of antibiotics, quinolones and aminopenicillins, which enhance WT torsinA activity in two separate in vivo assays. Representative molecules were assayed in EOTD patient fibroblasts for improvements in torsinA-dependent secretory function, which was improved significantly by ampicillin. Furthermore, a behavioral defect associated with an EOTD mouse knock-in model was also rescued following administration of ampicillin. These combined data indicate that specific small molecules that enhance torsinA activity represent a promising new approach toward therapeutic development for EOTD, and potentially for other diseases involving the processing of mutant proteins.

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Down‐regulation of torp4a, encoding the Drosophila homologue of torsinA, results in increased neuronal degeneration

Cited by 38 publications

References 64 publications

Invertebrate Models of Dystonia

Invertebrate Models of Dystonia

The Dystonia-associated Protein TorsinA Modulates Synaptic Vesicle Recycling

Chemical enhancement of torsinA function in cell and animal models of torsion dystonia

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