Transcriptional and proteomic profiling in a cellular model of DYT1 dystonia.
DYT1, the most common inherited dystonia, is caused by a common dominant mutation in the TOR1A gene that leads to a glutamic acid deletion in the protein torsinA. Wild-type torsinA locates preferentially in the endoplasmic reticulum while the disease-linked mutant accumulates in the nuclear envelope. As a result, it has been proposed that DYT1 pathogenesis could result either from transcriptional dysregulation caused by abnormal interactions of mutant torsinA with nuclear envelope proteins, or from a loss of torsinA function in the endoplasmic reticulum that would impair specific neurobiological pathways. Aiming to determine whether one or both of these potential mechanisms are implicated in DYT1 pathogenesis, we completed unbiased transcriptional and proteomic profiling in well-characterized neural cell lines that inducibly express wild-type or mutant torsinA. These experiments demonstrated that the accumulation of mutant torsinA in the nuclear envelope is not sufficient to cause transcriptional dysregulation. However, we detected expression changes at the protein level that, together with other reports, suggest a potential implication of torsinA on energy metabolism and regulation of the redox state. Furthermore, several proteins identified in this study have been previously linked to other forms of dystonia. In conclusion, our results argue against the hypothesis of transcriptional dysregulation in DYT1 dystonia, suggesting potential alternative pathogenic pathways.
Martin
J N
JN
Graduate Program in Genetics, The University of Iowa, Iowa City, IA, USA.
Bair
T B
TB
Bode
N
N
Dauer
W T
WT
Gonzalez-Alegre
P
P
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D020821:Dystonic Disorders / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism; D017354:Point Mutation; D040901:Proteomics / Q000379:methods; D051381:Rats; D014158:Transcription, Genetic
D018832:Molecular Chaperones; C108175:TOR1A protein, human