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...

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Bibliographic Details
Published in:PloS one 2014-11, Vol.9 (11), p.e110086
Main Authors: Cho, Jin A, Zhang, Xuan, Miller, Gregory M, Lencer, Wayne I, Nery, Flavia C
Format: Article
Language:English
Subjects:
Abnormalities
Adenylate cyclase
Age
Analysis
Animals
Biology and Life Sciences
Brain research
Cell adhesion & migration
Cell culture
Cell Line
Clonal deletion
Coding
Cyclic AMP
Cyclic AMP - metabolism
Defects
Disease
Dopamine
Down-Regulation - drug effects
Dystonia
Dystonia Musculorum Deformans - drug therapy
Dystonia Musculorum Deformans - metabolism
Dystonia Musculorum Deformans - pathology
Embryos
Endoplasmic reticulum
Endoplasmic Reticulum Stress - drug effects
Fibroblasts
Forskolin
Gastroenterology
Glutamate
Glutamic acid
Hospitals
Humans
Kinases
Laboratory animals
Medical schools
Memory
Mice
Molecular Chaperones - metabolism
Movement disorders
Muscles
Mutation
Nervous system diseases
Neurophysiology
Neurosciences
Pharmacology
Phenylbutyrates - pharmacology
Phenylbutyrates - therapeutic use
Phenylbutyric acid
Proteins
Rodents
Signal transduction
Signal Transduction - drug effects
Signaling
Stress
Stress response
Stresses
Studies
Twisting
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0110086