Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/87080
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Type: Journal article
Title: The BiP molecular chaperone plays multiple roles during the biogenesis of torsinA, an AAA⁺ ATPase associated with the neurological disease early-onset torsion dystonia
Other Titles: The BiP molecular chaperone plays multiple roles during the biogenesis of torsinA, an AAA(+) ATPase associated with the neurological disease early-onset torsion dystonia
Author: Zacchi, L.
Wu, H.
Bell, S.
Millen, L.
Paton, A.
Paton, J.
Thomas, P.
Zolkiewski, M.
Brodsky, J.
Citation: Journal of Biological Chemistry, 2014; 289(18):12727-12747
Publisher: American Society for Biochemistry and Molecular Biology
Issue Date: 2014
ISSN: 0021-9258
1083-351X
Statement of
Responsibility: 
Lucía F. Zacchi, Hui-Chuan Wu, Samantha L. Bell, Linda Millen, Adrienne W. Paton, James C. Paton, Philip J. Thomas, Michal Zolkiewski and Jeffrey L. Brodsky
Abstract: Early-onset torsion dystonia (EOTD) is a neurological disorder characterized by involuntary and sustained muscle contractions that can lead to paralysis and abnormal posture. EOTD is associated with the deletion of a glutamate (ΔE) in torsinA, an endoplasmic reticulum (ER) resident AAA(+) ATPase. To date, the effect of ΔE on torsinA and the reason that this mutation results in EOTD are unclear. Moreover, there are no specific therapeutic options to treat EOTD. To define the underlying biochemical defects associated with torsinAΔE and to uncover factors that might be targeted to offset defects associated with torsinAΔE, we developed a yeast torsinA expression system and tested the roles of ER chaperones in mediating the folding and stability of torsinA and torsinAΔE. We discovered that the ER lumenal Hsp70, BiP, an associated Hsp40, Scj1, and a nucleotide exchange factor, Lhs1, stabilize torsinA and torsinAΔE. BiP also maintained torsinA and torsinAΔE solubility. Mutations predicted to compromise specific torsinA functional motifs showed a synthetic interaction with the ΔE mutation and destabilized torsinAΔE, suggesting that the ΔE mutation predisposes torsinA to defects in the presence of secondary insults. In this case, BiP was required for torsinAΔE degradation, consistent with data that specific chaperones exhibit either pro-degradative or pro-folding activities. Finally, using two independent approaches, we established that BiP stabilizes torsinA and torsinAΔE in mammalian cells. Together, these data define BiP as the first identified torsinA chaperone, and treatments that modulate BiP might improve symptoms associated with EOTD.
Keywords: Molecular Chaperone; Neurological Diseases; Protein Degradation; Protein Folding; Yeast; BiP; DYT1; GRP78; torsinA
Rights: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
RMID: 0030008804
DOI: 10.1074/jbc.M113.529123
Appears in Collections:Molecular and Biomedical Science publications

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