Gnal haploinsufficiency causes genomic instability and increased sensitivity to haloperidol
GNAL encodes guanine nucleotide-binding protein subunit Gα(olf)which plays a key role in striatal medium spiny neuron (MSN)-dopamine signaling. GNAL loss-of-function mutations are causally-associated with isolated dystonia, a movement disorder characterized by involuntary muscle contractions leading to abnormal postures. Dopamine D2 receptor (D2R)blockers such as haloperidol are mainstays in the treatment of psychosis but may contribute to the development of secondary acute and tardive dystonia. Administration of haloperidol promotes cAMP-dependent signaling in D2R-expressing indirect pathway MSNs. At present, little is known about the cellular relationships among isolated, acute, and tardive dystonia. Herein, we report the effects of acute D2R blockade on motor behavior, DNA repair, cAMP-mediated histone H3 phosphorylation (Ser10), and cell death in Gnal+/− mice and their isogenic Gnal+/+ littermates. In comparison to Gnal+/+ littermates, Gnal+/− mice exhibited increased catalepsy responses, persistent DNA breaks, decreased cAMP-dependent histone H3 phosphorylation (Ser10), and increased cell death in response to haloperidol. In striatum, aged Gnal+/− mice exhibited increased global DNA methylation, increased euchromatin, and dendritic structural abnormalities. Our results provide evidence that Gα(olf)deficiency intensifies the effects of D2R antagonism and suggests that loss-of-function variants in GNAL may increase risk for movement disorders associated with D2R blockers. We hypothesize that the effects of Gα(olf)dysfunction and/or long-term D2R antagonism may lead to epigenetic silencing, transcriptional dysregulation, and, ultimately, cellular senescence and/or apoptosis in human brain.
Khan, M., Xiao, J., Hollingsworth, T., Patel, D., Selley, D., Ring, T., & LeDoux, M. (2019). Gnal haploinsufficiency causes genomic instability and increased sensitivity to haloperidol. Experimental Neurology, 318, 61-70. https://doi.org/10.1016/j.expneurol.2019.04.014