The early-onset torsion dystonia-associated protein, torsinA, is a homeostatic regulator of endoplasmic reticulum stress response.
Early-onset torsion dystonia is the most severe heritable form of dystonia, a human movement disorder that typically starts during a developmental window in early adolescence. Deletion in the DYT1 gene, encoding the torsinA protein, is responsible for this dominantly inherited disorder, which is non-degenerative and exhibits reduced penetrance among carriers. Here, we explore the hypothesis that deficits in torsinA function result in an increased vulnerability to stress associated with protein folding and processing in the endoplasmic reticulum (ER), where torsinA is located. Using an in vivo quantitative readout for the ER stress response, we evaluated the consequences of torsinA mutations in transgenic nematodes expressing variants of human torsinA. This analysis revealed that, normally, torsinA serves a protective function to maintain a homeostatic threshold against ER stress. Furthermore, we show that the buffering capacity of torsinA is greatly diminished by the DYT1-associated deletion or mutations that prevent its translocation to the ER, block ATPase activity, or increase the levels of torsinA in the nuclear envelope versus ER. Combinations of transgenic Caenorhabditis elegans designed to mimic clinically relevant genetic modifiers of disease susceptibility also exhibit a direct functional correlation to changes in the ER stress response. Furthermore, using mouse embryonic fibroblasts (MEFs) from torsinA knockout mice, we demonstrated that loss of endogenous torsinA results in enhanced sensitivity to ER stress. This study extends our understanding of molecular mechanisms underlying dystonia, and establishes a new functional paradigm to evaluate therapeutic strategies to compensate for reduced torsinA activity in the ER as a means to restore homeostatic balance and neuronal function.
Chen
Pan
P
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA.
Burdette
Alexander J
AJ
Porter
J Christopher
JC
Ricketts
John C
JC
Fox
Stacey A
SA
Nery
Flavia C
FC
Hewett
Jeffrey W
JW
Berkowitz
Laura A
LA
Breakefield
Xandra O
XO
Caldwell
Kim A
KA
Caldwell
Guy A
GA
D017668:Age of Onset; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004421:Dystonia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D013312:Stress, Physiological
C491548:Dyt1 protein, mouse; D018832:Molecular Chaperones; C108175:TOR1A protein, human