The ER chaperones BiP and Jem1/Scj1 are genetic modifiers of TorsinA, the AAA+ ATPase associated with the neurological disease primary torsion dystonia

Abstract

Dystonia is a disease characterized by involuntary and sustained muscle contractions that lead to paralysis and abnormal postures. The most severe type of dystonia, early‐onset Torsion dystonia, is associated with a deletion of a glutamate (ΔE) near the C‐terminus in TorsinA. TorsinA is an endoplasmic reticulum (ER) AAA+ ATPase of ill‐defined function, and the reasons that the ΔE variant is associated with the disease are unclear. Further, the penetrance of the disease is highly variable, suggesting that genetic modifiers affect disease severity. In order to identify modifiers of TorsinA stability and folding, we developed a TorsinA expression system in Saccharomyces cerevisiae. Similar to TorsinA in mammalian cells, TorsinA and TorsinAΔE in yeast associate with the luminal side of the ER membrane and are glycosylated. We found that the stability and glycosylation of TorsinA and TorsinAΔE depend on the yeast ER Hsp70 chaperone BiP and Hsp40 co‐chaperones Jem1 and Scj1. Mutations in TorsinA that prevent glycosylation, ATP binding, or ATP hydrolysis, or that eliminate the hydrophobic domain led to BiP‐dependent degradation, and to differences in protease sensitivity and membrane association. Therefore, we have identified conserved ER chaperones that are critical for TorsinA conformation and stability. We are testing these findings in mammalian systems. Supported by the Dystonia Medical Research Foundation.