TorsinA protein degradation and autophagy in DYT1 dystonia

Giles, Lisa M.; Li, Lian; Chin, Lih‐Shen

doi:10.4161/auto.5.1.7173

Cited by 12 publications

(8 citation statements)

References 30 publications

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“…TorsinA disrupts ER/NE and cytoskeletal dynamics, which may be important for neurite extension during brain development49–53 and has also been implicated in synaptic vesicle recycling, including impaired dopamine release54–57 and alter tyrosine hydroxylase activity 58. Exactly how torsinA function is compromised to produce disease is unknown, but both animal and cellular studies indicate that mutant torsinA results in a loss of function 49, 54, 59–61…”

Section: Geneticsmentioning

confidence: 99%

Deleterious Effects of Beta-Blockers on Survival in Patients With Cirrhosis and Refractory Ascites†,‡

Mélot²,

et al. 2010

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Beta-blockers may have a negative impact on survival in patients with cirrhosis and refractory ascites. The aim of this study was to evaluate the effect of the administration of betablockers on long-term survival in patients with cirrhosis and refractory ascites. We performed a single-center, observational, case-only, prospective study of patients with cirrhosis and refractory ascites who did or did not receive beta-blockers for the prevention of gastrointestinal bleeding; 151 patients were included. The mean Model for End-Stage Liver Disease score was 18.8 6 4.1. All patients regularly underwent large-volume paracentesis and intravenous albumin administration. Seventy-seven patients (51%) were treated with propranolol (113 6 46 mg/day). The median follow-up for the whole group was 8 months. The median survival time was 10 months [95% confidence interval (CI) 5 8-12 months]. The probability of survival at 1 year was 41% (95% CI 5 33%-49%). The clinical characteristics and laboratory values at enrolment were not significantly different between patients who were receiving propranolol and those who were not. The median survival time was 20.0 months (95% CI 5 4.8-35.2 months) in patients not treated with propranolol and 5.0 months (95% CI 5 3.5-6.5 months) in those treated with propranolol (P 5 0.0001). The 1-year probability of survival was significantly lower in patients who received propranolol [19% (95% CI 5 9%-29%)] versus those who did not [64% (95% CI 5 52%-76%), P < 0.0001]. The independent variables of mortality were Child-Pugh class C, hyponatremia and renal failure as causes of refractory ascites, and beta-blocker therapy. Conclusion: The use of beta-blockers is associated with poor survival in patients with refractory ascites. These results suggest that betablockers should be contraindicated in these patients.

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Section: Geneticsmentioning

confidence: 99%

Deleterious Effects of Beta-Blockers on Survival in Patients With Cirrhosis and Refractory Ascites†,‡

Mélot²,

et al. 2010

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“…Cdc48/p97 AAA ϩ ATPase regulates membrane fusion through interaction with its cofactor p47, and participates in the ER-associated degradation process by forming a complex with its cofactors, Ufd1 and Npl4 (68). Given that torsinA is a 332-amino acid protein with a 220-amino acid AAA ϩ ATPase homology domain and 40-amino acid hydrophobic regions (69), it seems particularly plausible that torsinA ATPase would use co-factor(s) to extend its binding repertoire for substrate recognition and function regulation. Printor, with its multiple protein-protein interaction domains, could either directly recruit torsinA substrates or act as a scaffold for organizing a multicomponent torsinAchaperone complex.…”

Section: Discussionmentioning

confidence: 99%

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Giles

Chin

2009

Journal of Biological Chemistry

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Early onset generalized dystonia (DYT1) is an autosomal dominant neurological disorder caused by deletion of a single glutamate residue (torsinA ⌬E) in the C-terminal region of the AAA ؉ (ATPases associated with a variety of cellular activities) protein torsinA. The pathogenic mechanism by which torsinA ⌬E mutation leads to dystonia remains unknown. Here we report the identification and characterization of a 628-amino acid novel protein, printor, that interacts with torsinA. Printor co-distributes with torsinA in multiple brain regions and colocalizes with torsinA in the endoplasmic reticulum. Interestingly, printor selectively binds to the ATP-free form but not to the ATP-bound form of torsinA, supporting a role for printor as a cofactor rather than a substrate of torsinA. The interaction of printor with torsinA is completely abolished by the dystoniaassociated torsinA ⌬E mutation. Our findings suggest that printor is a new component of the DYT1 pathogenic pathway and provide a potential molecular target for therapeutic intervention in dystonia.Early onset generalized torsion dystonia (DYT1) is the most common and severe form of hereditary dystonia, a movement disorder characterized by involuntary movements and sustained muscle spasms (1). This autosomal dominant disease has childhood onset and its dystonic symptoms are thought to result from neuronal dysfunction rather than neurodegeneration (2, 3). Most DYT1 cases are caused by deletion of a single glutamate residue at positions 302 or 303 (torsinA ⌬E) of the 332-amino acid protein torsinA (4). In addition, a different torsinA mutation that deletes amino acids Phe 323 -Tyr 328(torsinA ⌬323-328) was identified in a single family with dystonia (5), although the pathogenic significance of this torsinA mutation is unclear because these patients contain a concomitant mutation in another dystonia-related protein, ⑀-sarcoglycan (6). Recently, genetic association studies have implicated polymorphisms in the torsinA gene as a genetic risk factor in the development of adult-onset idiopathic dystonia (7,8).TorsinA contains an N-terminal endoplasmic reticulum (ER) 3 signal sequence and a 20-amino acid hydrophobic region followed by a conserved AAA ϩ (ATPases associated with a variety of cellular activities) domain (9, 10). Because members of the AAA ϩ family are known to facilitate conformational changes in target proteins (11,12), it has been proposed that torsinA may function as a molecular chaperone (13,14). TorsinA is widely expressed in brain and multiple other tissues (15) and is primarily associated with the ER and nuclear envelope (NE) compartments in cells (16 -20). TorsinA is believed to mainly reside in the lumen of the ER and NE (17-19) and has been shown to bind lamina-associated polypeptide 1 (LAP1) (21), lumenal domain-like LAP1 (LULL1) (21), and nesprins (22). In addition, recent evidence indicates that a significant pool of torsinA exhibits a topology in which the AAA ϩ domain faces the cytoplasm (20). In support of this topology, torsinA is found in the...

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“…Initial biophysical analyses detected no significant differences between wild-type torsinA and torsinAΔE to suggest that the missing glutamic acid would result in gross protein misfolding (Kustedjo et al, 2003). More recent comparisons reported that torsinA and torsinAΔE were processed by different degradation pathways, with the mutant protein selectively targeted for destruction by the proteosome (Gordon and Gonzalez-Alegre, 2008; Giles et al, 2008 and 2009). That observation suggests that torsinAΔE displays unique structural features that not only distinguish it from the wild-type protein but also selectively trigger the proteosomal pathway.…”

Section: Endoplasmic Reticulum Stressmentioning

confidence: 99%

Molecular pathways in dystonia

Bragg

Armata

Nery

et al. 2011

Neurobiology of Disease

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The hereditary dystonias comprise a set of diseases defined by a common constellation of motor deficits. These disorders are most likely associated with different molecular etiologies, many of which have yet to be elucidated. Here we discuss recent advances in three forms of hereditary dystonia, DYT1, DYT6 and DYT16, which share a similar clinical picture: onset in childhood or adolescence, progressive spread of symptoms with generalized involvement of body regions and a steady state affliction without treatment. Unlike DYT1, the genes responsible for DYT6 and DYT16 have only recently been identified, with relatively little information about the function of the encoded proteins. Nevertheless, recent data suggest that these proteins may fit together within interacting pathways involved in dopaminergic signaling, transcriptional regulation, and cellular stress responses. This review focuses on these molecular pathways, highlighting potential common themes among these dystonias which may serve as areas for future research.

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TorsinA protein degradation and autophagy in DYT1 dystonia

Cited by 12 publications

References 30 publications

Deleterious Effects of Beta-Blockers on Survival in Patients With Cirrhosis and Refractory Ascites†,‡

Deleterious Effects of Beta-Blockers on Survival in Patients With Cirrhosis and Refractory Ascites†,‡

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Molecular pathways in dystonia

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