4-Phenylbutyrate attenuates the ER stress response and cyclic AMP accumulation in DYT1 dystonia cell models.

Jin A Cho,Flavia C Nery,Wayne I Lencer,Gregory M Miller,Xuan Zhang

doi:10.1371/journal.pone.0110086

Abstract

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.

Highlights

The DYT1 early-onset primary dystonia is the most severe form of hereditary dystonia and is caused by a mutation in the gene, TOR1A (DYT1), encoding torsinA protein [1]
We first observed a potential relationship between mutant torsinA and adenylate cyclase during our studies using cholera toxin to examine the role torsinA might play in endoplasmic reticulum-associated degradation (ERAD) [24]
How these two pathways are linked mechanistically remains unclear, but it is possible though that the endoplasmic reticulum (ER) stress induced by mutant torsinA in patients with DYT1 dystonia contributes to neuronal dysfunction through a cAMP defect (Figure 5)

Summary

Introduction

The DYT1 early-onset primary dystonia is the most severe form of hereditary dystonia and is caused by a mutation in the gene, TOR1A (DYT1), encoding torsinA protein [1]. Current treatments include high dose anticholinergics, which are only partially effective and can compromise learning and memory [2] Another available treatment for dystonia is deep brain stimulation (DBS), which involves an implant of stimulating electrodes into the basal ganglia [3]. Many studies at the biochemical, structural, and cell biological levels have been performed in order to characterize torsinA [5,6] These studies, together with the generation of several animal models [7,8,9], have contributed to the identification of cellular compartments and pathways affected by mutant torsinA, including the nuclear envelope (NE) [10,11], cytoskeleton [12,13], cell migration [12,14], secretory pathway [15,16,17,18], dopamine pathway [5,19,20,21,22], synaptic vesicle recycling [22], endoplasmic reticulum (ER) stress [23,24], and endoplasmic reticulum-associated degradation (ERAD) [24,25], where torsinA’s function may be crucial for the cell homeostasis

Methods

Results

Conclusion