Straightjacket/α2δ3 deregulation is associated with cardiac conduction defects in myotonic dystrophy type 1

Cardiac conduction defects decrease life expectancy in myotonic dystrophy type 1 (DM1), a CTG repeat disorder involving misbalance between two RNA binding factors, MBNL1 and CELF1. However, how DM1 condition translates into conduction disorders remains poorly understood. Here we simulated MBNL1 and CELF1 misbalance in the Drosophila heart and performed TU-tagging-based RNAseq of cardiac cells. We detected deregulations of several genes controlling cellular calcium levels, including increased expression of straightjacket/α2δ3, which encodes a regulatory subunit of a voltage-gated calcium channel. Straightjacket overexpression in the fly heart leads to asynchronous heartbeat, a hallmark of abnormal conduction, whereas cardiac straightjacket knockdown improves these symptoms in DM1 fly models. We also show that ventricular α2δ3 expression is low in healthy mice and humans, but significantly elevated in ventricular muscles from DM1 patients with conduction defects. These findings suggest that reducing ventricular straightjacket/α2δ3 levels could offer a strategy to prevent conduction defects in DM1.

Are Atypical Antipsychotics the Least Detrimental Alternative?

Antipsychotics are typically used for the treatment of schizophrenia, bipolar disorder, and recently, treatment resistant major depressive disorder. A significant, and very concerning, side effect present with first generation antipsychotics is extrapyramidal symptoms, which are disorders of movement. With the advent of atypical antipsychotics, also known as second-generation antipsychotics, these symptoms are purported to be much less frequent and pronounced than they were with the first generation medications. Numerous hypotheses have been proposed as to why atypical antipsychotics produce fewer extrapyramidal symptoms compared to first generation antipsychotics, which this paper will review. Unfortunately, despite the fact that atypicals have reduced extrapyramidal symptoms in those taking antipsychotics, extrapyramidal symptoms are still an unpleasant and potentially dangerous side effect, which can be difficult to detect, and difficult, or even impossible, to treat. Additionally, atypical antipsychotics result in other potentially very serious side effects, specifically and most commonly, metabolic syndrome, which can decrease life expectancy significantly. However, metabolic syndrome, unlike extrapyramidal symptoms, may be preventable in highly motivated and well-supported patients. Thus, this paper concludes that the benefits of the atypical antipsychotics (reduced extrapyramidal symptoms) outweigh the potential risks for the majority of patients.