TorsinA protein degradation and autophagy in DYT1 dystonia

Abstract

Early-onset generalized dystonia (DYT1) is a debilitating neurological disorder characterized by involuntary movements and sustained muscle spasms. DYT1 dystonia has been associated with two mutations in torsinA that result in the deletion of a single glutamate residue (torsinA DeltaE) and six amino-acid residues (torsinA Delta323-8). We recently revealed that torsinA, a peripheral membrane protein, which resides predominantly in the lumen of the endoplasmic reticulum (ER) and nuclear envelope (NE), is a long-lived protein whose turnover is mediated by basal autophagy. Dystonia-associated torsinA DeltaE and torsinA Delta323-8 mutant proteins show enhanced retention in the NE and accelerated degradation by both the proteasome and autophagy. Our results raise the possibility that the monomeric form of torsinA mutant proteins is cleared by proteasome-mediated ER-associated degradation (ERAD), whereas the oligomeric and aggregated forms of torsinA mutant proteins are cleared by ER stress-induced autophagy. Our findings provide new insights into the pathogenic mechanism of torsinA DeltaE and torsinA Delta323-8 mutations in dystonia and emphasize the need for a mechanistic understanding of the role of autophagy in protein quality control in the ER and NE compartments.

Figure 1

Degradation of torsinA wild-type (WT) and mutant proteins by autophagy. (A) Domain structure of TorsinA. S, ER signal sequence; H, hydrophobic domain; AAA⁺, ATPases associated with a variety of cellular activities. The locations of dystonia-associated torsinA mutations are indicated on the domain structure. (B) Potential mechanisms for clearance of torsinA WT and mutant proteins. TorsinA WT is recruited to a subdomain of the ER that is sequestered into an autophagosome for lysosomal degradation by basal autophagy. The ER-localized, monomeric form of torsinA mutant proteins are retrotranslocated to the cytosol by ERAD for degradation by the cytosolic proteasome, whereas the nuclear envelope (NE)-localized, monomeric form of torsinA mutant proteins may be retrotranslocated to the nucleus by the inner nuclear membrane-associated ERAD for degradation by the nuclear proteasome. It is also possible that the NE-localized torsinA mutant monomers are retrotranslocated to the cytosol by the outer nuclear membrane-associated ERAD or the mutants may have to migrate to the ER for ERAD-mediated degradation by the cytosolic proteasome. The ER-localized, oligomeric and aggregated forms of torsinA mutant proteins may segregate in a specialized area of the ER for clearance by ER stressinduced autophagy, whereas the NE-localized, oligomeric and aggregated forms of torsinA mutant proteins may be cleared by autophagy via an unknown mechanism.