The BiP molecular chaperone plays multiple roles during the biogenesis of TorsinA, a AAA+ ATPase associated with the neurological disease Early-Onset Torsion Dystonia.

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 (E) in TorsinA, an ER resident AAA+ ATPase. To date, the effect of E 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 TorsinAE and to uncover factors that might be targeted to offset defects associated with TorsinAE, we developed a yeast TorsinA expression system and tested the roles of ER chaperones in mediating the folding and stability of TorsinA and TorsinAE. We discovered that the ER lumenal Hsp70, BiP, an associated Hsp40, Scj1, and a nucleotide exchange factor, Lhs1, stabilize TorsinA and TorsinAE. BiP also maintained TorsinA and TorsinAE solubility. Mutations predicted to compromise specific TorsinA functional motifs showed a synthetic interaction with the E mutation and destabilized TorsinAE, suggesting that the E mutation predisposes TorsinA to defects in the presence of secondary insults. In this case, BiP was required for TorsinAE 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 TorsinAE 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.