Dystonia-associated mutations cause premature degradation of torsinA protein and cell-type-specific mislocalization to the nuclear envelope.
An in-frame 3 bp deletion in the torsinA gene resulting in the loss of a glutamate residue at position 302 or 303 (torsinA DeltaE) is the major cause for early-onset torsion dystonia (DYT1). In addition, an 18 bp deletion in the torsinA gene resulting in the loss of residues 323-328 (torsinA Delta323-8) has also been associated with dystonia. Here we report that torsinA DeltaE and torsinA Delta323-8 mutations cause neuronal cell-type-specific mislocalization of torsinA protein to the nuclear envelope without affecting torsinA oligomerization. Furthermore, both dystonia-associated mutations destabilize torsinA protein in dopaminergic cells. We find that wild-type torsinA protein is degraded primarily through the macroautophagy-lysosome pathway. In contrast, torsinA DeltaE and torsinA Delta323-8 mutant proteins are degraded by both the proteasome and macroautophagy-lysosome pathways. Our findings suggest that torsinA mutation-induced premature degradation may contribute to the pathogenesis of dystonia via a loss-of-function mechanism and underscore the importance of both the proteasome and macroautophagy in the clearance of dystonia-associated torsinA mutant proteins.
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322-3090, USA.
Lisa M
LM
Giles
Jue
J
Chen
Lian
L
Li
Lih-Shen
LS
Chin
D001343:Autophagy; D002460:Cell Line; D004421:Dystonia / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
D018832:Molecular Chaperones; C108175:TOR1A protein, human; D046988:Proteasome Endopeptidase Complex