4-Phenylbutyrate Attenuates the ER Stress Response and Cyclic AMP Accumulation in DYT1 Dystonia Cell Models

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.

Cilostazol ameliorates ischemia/reperfusion‐induced tight junction disruption in brain endothelial cells by inhibiting endoplasmic reticulum stress

“…These changes can be reversed by treatment with cilostazol but not ER stress inhibitor. Although it has been proposed that treatment with 4-PBA attenuates the ER stress response and rescued cAMP accumulation deficiency in DYT1 (hereditary dystonia caused by mutation in the TOR1A gene) patient fibroblast lines comparable to control fibroblast cAMP levels (39), our results present no change in cAMP levels after treatment with 4-PBA in our model. This may be because the concentration of 4-PBA they used in their experiment was much higher (5 mM) than that in our experiment (100 mM).…”

The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis

“…4-PBA treatment reduced thapsigargin induced ER stress and adenylate cyclase activity in DYT1 cell lines. This suggests a potential therapeutic effect of 4-PBA in treating dystonia (Cho et al, 2014).…”

Phenotypic insights into ADCY5 ‐associated disease

“…Mutations in the Tor1A gene are the most common genetic cause of childhood‐onset generalized dystonia. Cellular models suggest that the Tor1A gene mutation induces inhibition of the cyclic adenosine monophosphate response to an adenylyl cyclase 5 agonist . DYT25 causes adult‐onset generalized dystonia attributed to loss of function in the GNAL gene .…”

“…Cellular models suggest that the Tor1A gene mutation induces inhibition of the cyclic adenosine monophosphate response to an adenylyl cyclase 5 agonist. 42 DYT25 causes adult-onset generalized dystonia attributed to loss of function in the GNAL gene. 43,44 This gene codes for guanine nucleotide-binding protein, alpha-activating activity polypeptide, olfactory type [Ga(olf)], which is abundant in the striatum 45 ).…”