TorsinA (TorA) is an AAA+ (ATPases associated with diverse cellular activities) ATPase linked to dystonia type 1 (DYT1), a neurological disorder that leads to uncontrollable muscular movements. Although DYT1 is linked to a 3 bp deletion in the C-terminus of TorA, the biological function of TorA remains to be established. Here, we use the yeast Saccharomyces cerevisiae as a tractable in vivo model to explore TorA function. We demonstrate that TorA can protect yeast cells against different forms of environmental stress and show that in the absence of the molecular disaggregase Hsp104, TorA can refold heat-denatured luciferase in vivo in an ATP-dependent manner. However, this activity requires TorA to be translocated to the cytoplasm from the endoplasmic reticulum in order to access and process cytoplasmic protein aggregates. Furthermore, mutational or chemical inactivation of the ATPase activity of TorA blocks this activity. We also find that TorA can inhibit the propagation of certain conformational variants of [PSI⁺], the aggregated prion form of the endogenous Sup35 protein. Finally, we show that while cellular localisation remains unchanged in the dystonia-linked TorA mutant ΔE302-303, the ability of this mutant form of TorA to protect against cellular stress and to facilitate protein refolding is impaired, consistent with it being a loss-of-function mutation.

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Journal Article

Authors

Adam I, Jossé L, Tuite MF

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