Dystonia-associated mutations cause premature degradation of torsinA protein and cell-type-specific mislocalization to the nuclear envelope.
Hum Mol Genet
; 17(17): 2712-22, 2008 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-18552369
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Chaperonas Moleculares
/
Distonia
/
Membrana Nuclear
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Hum Mol Genet
Ano de publicação:
2008
Tipo de documento:
Article