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

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

doi:10.1074/jbc.m109.004838

Cited by 30 publications

(31 citation statements)

References 72 publications

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“…As others have found, the torsinA family also lacks this critical residue. It remains possible, however, that torsinA may require some unknown cofactor to activate its ATPase activity, as previously suggested (Zhu et al 2008;Giles et al 2009). This in turn could influence its chaperone abilities, although further studies will be needed to test this hypothesis.…”

Section: Discussionmentioning

confidence: 88%

“…Furthermore, we did not obtain any detectable level of ATPase activity with WT torsinA or torsinA (ΔE); both of these were compared to the negative control, the torsinA E171Q hydrolysis mutant (data not shown). This suggests that ATP does not affect the chaperone function of torsinA alone, but may require the addition of a cofactor to activate its ATPase activity and influence its chaperone abilities as others have suggested (Zhu et al 2008;Giles et al 2009). …”

Section: Atp Does Not Affect the Chaperone Function Of Torsinamentioning

confidence: 86%

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The early-onset torsion dystonia-associated protein, torsinA, displays molecular chaperone activity in vitro

Burdette

Churchill

Caldwell

et al. 2010

Cell Stress and Chaperones

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TorsinA is a member of the AAA+ ATPase family of proteins and, notably, is the only known ATPase localized to the ER lumen. It has been suggested to act as a molecular chaperone, while a mutant form associated with early-onset torsion dystonia, a dominantly inherited movement disorder, appears to result in a net loss of function in vivo. Thus far, no studies have examined the chaperone activity of torsinA in vitro. Here we expressed and purified both wild-type (WT) and mutant torsinA fusion proteins in bacteria and examined their ability to function as molecular chaperones by monitoring suppression of luciferase and citrate synthase (CS) aggregation. We also assessed their ability to hold proteins in an intermediate state for refolding. As measured by light scattering and SDS-PAGE, both WT and mutant torsinA effectively, and similarly, suppressed protein aggregation compared to controls. This function was not further enhanced by the presence of ATP. Further, we found that while neither form of torsinA could protect CS from heat-induced inactivation, they were both able to reactivate luciferase when ATP and rabbit reticulocyte lysate were added. This suggests that torsinA holds luciferase in an intermediate state, which can then be refolded in the presence of other chaperones. These data provide conclusive evidence that torsinA acts as a molecular chaperone in vitro and suggests that early-onset torsion dystonia is likely not a consequence of a loss in torsinA chaperone activity but might be an outcome of insufficient torsinA localization at the ER to manage protein folding or trafficking.

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Section: Discussionmentioning

confidence: 88%

Section: Atp Does Not Affect the Chaperone Function Of Torsinamentioning

confidence: 86%

The early-onset torsion dystonia-associated protein, torsinA, displays molecular chaperone activity in vitro

Burdette

Churchill

Caldwell

et al. 2010

Cell Stress and Chaperones

View full text Add to dashboard Cite

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“…These data raise the possibilities that torsinA is involved in regulating the spatial localization of HRD1 within the ER/NE endomembrane space and that HRD1 mislocalization contributes to torsinAmediated neurodegeneration. Spatial regulation of an E3 ubiquitin ligase within the ER/NE space has been demonstrated in yeast (47), and torsinA has binding partners in both of these locations (18,20,48). Indeed, one effect of the ΔE mutation is to disrupt the distribution of torsinA between these 2 compartments (7,17,19).…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration

et al. 2014

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Lack of a preclinical model of primary dystonia that exhibits dystonic-like twisting movements has stymied identification of the cellular and molecular underpinnings of the disease. The classical familial form of primary dystonia is caused by the DYT1 (ΔE) mutation in TOR1A, which encodes torsinA, AAA + ATPase resident in the lumen of the endoplasmic reticular/nuclear envelope. Here, we found that conditional deletion of Tor1a in the CNS (nestin-Cre Tor1a flox/-) or isolated CNS expression of DYT1 mutant torsinA (nestin-Cre Tor1a flox/ΔE ) causes striking abnormal twisting movements. These animals developed perinuclear accumulation of ubiquitin and the E3 ubiquitin ligase HRD1 in discrete sensorimotor regions, followed by neurodegeneration that was substantially milder in nestin-Cre Tor1a flox/ΔE compared with nestin-Cre Tor1a flox/-animals. Similar to the neurodevelopmental onset of DYT1 dystonia in humans, the behavioral and histopathological abnormalities emerged and became fixed during CNS maturation in the murine models. Our results establish a genetic model of primary dystonia that is overtly symptomatic, and link torsinA hypofunction to neurodegeneration and abnormal twisting movements. These findings provide a cellular and molecular framework for how impaired torsinA function selectively disrupts neural circuits and raise the possibility that discrete foci of neurodegeneration may contribute to the pathogenesis of DYT1 dystonia. IntroductionThe primary dystonias, a group of sporadic and inherited illnesses, are a striking example of selective vulnerability of CNS sensorimotor circuits (1, 2). Dystonia -defined as prolonged, involuntary twisting movements -is traditionally classified as "primary" if it occurs in isolation and in the absence of neuropathological change. In contrast, "secondary" dystonic movements occur consequent to CNS damage (e.g., from stroke, trauma, or neurodegeneration), and are typically accompanied by additional neurological signs and symptoms. This classification scheme has been criticized (3), however, because neuroimaging of patients with primary dystonia indicates the presence of subtle neuropathological changes, and few primary dystonia brains have been comprehensively analyzed (4). Indeed, despite considerable interest in the pathophysiology of primary dystonia, the molecular and cellular underpinnings of CNS dysfunction and the identity of affected motor structures and cell types remain poorly understood. DYT1 dystonia is a common inherited form of primary dystonia that typically manifests during a discrete period of childhood, implicating abnormal development as the cause of motor dysfunction. This neurodevelopmental disease is caused by a 3 bp in-frame mutation in TOR1A that removes a single glutamic acid residue (ΔE) from the torsinA protein. TorsinA is a ubiquitously expressed AAA + protein residing in the lumen of the ER/nuclear envelope (ER/NE) space (5-7). Accumulating evidence indicates that the DYT1 mutation acts by impairing torsinA function through multiple mechan...

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“…Subcellular fractionations of HeLa, HEK293, or SH-SY5Y cells into membrane and cytosol fractions were performed as described (Giles et al, 2009). For membrane association analysis, membrane fractions were subjected to extraction with 1% Triton X-100 (TX-100), 4 M Urea, 1.5 M NaCl or 0.1 M Na 2 CO 3 (pH 11.5) for 1 hour.…”

Section: Subcellular Fractionation and Membrane Association Analysismentioning

confidence: 99%

Mutations associated with Charcot–Marie–Tooth disease cause SIMPLE protein mislocalization and degradation by the proteasome and aggresome–autophagy pathways

Lee

Olzmann

Chin

et al. 2011

Journal of Cell Science

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110

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SummaryMutations in SIMPLE cause an autosomal dominant, demyelinating form of peripheral neuropathy termed Charcot-Marie-Tooth disease type 1C (CMT1C), but the pathogenic mechanisms of these mutations remain unknown. Here, we report that SIMPLE is an early endosomal membrane protein that is highly expressed in the peripheral nerves and Schwann cells. Our analysis has identified a transmembrane domain (TMD) embedded within the cysteine-rich (C-rich) region that anchors SIMPLE to the membrane, and suggests that SIMPLE is a post-translationally inserted, C-tail-anchored membrane protein. We found that CMT1C-linked pathogenic mutations are clustered within or around the TMD of SIMPLE and that these mutations cause mislocalization of SIMPLE from the early endosome membrane to the cytosol. The CMT1C-associated SIMPLE mutant proteins are unstable and prone to aggregation, and they are selectively degraded by both the proteasome and aggresome-autophagy pathways. Our findings suggest that SIMPLE mutations cause CMT1C peripheral neuropathy by a combination of loss-of-function and toxic gain-of-function mechanisms, and highlight the importance of both the proteasome and autophagy pathways in the clearance of CMT1C-associated mutant SIMPLE proteins.

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

Cited by 30 publications

References 72 publications

The early-onset torsion dystonia-associated protein, torsinA, displays molecular chaperone activity in vitro

The early-onset torsion dystonia-associated protein, torsinA, displays molecular chaperone activity in vitro

TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration

Mutations associated with Charcot–Marie–Tooth disease cause SIMPLE protein mislocalization and degradation by the proteasome and aggresome–autophagy pathways

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