4-Phenylbutyrate attenuates the ER stress response and cyclic AMP accumulation in DYT1 dystonia cell models.
Dystonia is a neurological disorder in which sustained muscle contractions induce twisting and repetitive movements or abnormal posturing. DYT1 early-onset primary dystonia is the most common form of hereditary dystonia and is caused by deletion of a glutamic acid residue (302/303) near the carboxyl-terminus of encoded torsinA. TorsinA is localized primarily within the contiguous lumen of the endoplasmic reticulum (ER) and nuclear envelope (NE), and is hypothesized to function as a molecular chaperone and an important regulator of the ER stress-signaling pathway, but how the mutation in torsinA causes disease remains unclear. Multiple lines of evidence suggest that the clinical symptoms of dystonia result from abnormalities in dopamine (DA) signaling, and possibly involving its down-stream effector adenylate cyclase that produces the second messenger cyclic adenosine-3', 5'-monophosphate (cAMP). Here we find that mutation in torsinA induces ER stress, and inhibits the cyclic adenosine-3', 5'-monophosphate (cAMP) response to the adenylate cyclase agonist forskolin. Both defective mechanins are corrected by the small molecule 4-phenylbutyrate (4-PBA) that alleviates ER stress. Our results link torsinA, the ER-stress-response, and cAMP-dependent signaling, and suggest 4-PBA could also be used in dystonia treatment. Other pharmacological agents known to modulate the cAMP cascade, and ER stress may also be therapeutic in dystonia patients and can be tested in the models described here, thus supplementing current efforts centered on the dopamine pathway.
Division of Gastroenterology/Cell Biology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States of America.
Jin A
JA
Cho
Neuroscience Center, Department of Neurology, and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, MA, United States of America.
Xuan
X
Zhang
Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, MA, United States of America.
Gregory M
GM
Miller
Division of Gastroenterology/Cell Biology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States of America; Harvard Digestive Diseases Center, Harvard Medical School, Boston, MA, United States of America.
Wayne I
WI
Lencer
Neuroscience Center, Department of Neurology, and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, MA, United States of America.
Flavia C
FC
Nery
D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004422:Dystonia Musculorum Deformans / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
D018832:Molecular Chaperones; D010654:Phenylbutyrates; C108175:TOR1A protein, human; C075773:4-phenylbutyric acid; D000242:Cyclic AMP