| Keywords [eng] |
Drosophila Melanogaster, STRING, iGraph, DAMS, TL-PGR, HMGCR, Acetilcholinas, Neureksinas, Acetilcholino esterazė, Neostigminas. |
| Abstract [eng] |
Statins are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). This group of drugs is used to lower low-density lipoprotein cholesterol (LDL-C) and is one of the most effective drugs in decreasing the incidence of cardiovascular disease (Newman Connie B. et al., 2019). However, one of the major obstacles in preventing these diseases is discontinuation of statin treatment due to adverse effects. Statin-induced muscle symptoms (SAMS), which makes up to 72% of all statin adverse effects, is a Major major cause of treatment discontinuation (Ward et al., 2019). However, the mechanisms that relate statin treatment to SAMS is not clear. To study statin side effects, our lab used the model organism Drosophila melanogaster (further referred to as fly). Previous studies found that statin treatment impairs fly locomotory behavior (Williams lab, unpublished data). Therefore, it was presumed that this impaired locomotory behavior mimics the SAMS phenotype. This study tested the locomotory behavior of the fly model where HMGCR is knocked down in all neurons, which showed the impaired locomotory behavior. The findings led an investigation to elucidate the molecular reasons of impaired locomotory behavior, which presumably mimics statin-induced muscle symptoms. The impaired locomotion was partially recovered with the cholinesterase inhibitor neostigmine, therefore, I investigated the RNA expression of three fly homologues of human acetylcholine esterase (Ace, CG4757, CG4382), nicotinic acetylcholine receptor and an orthologue of human early growth response 1 - Stripe. In parallel, I used STRING protein interaction data to build a model that relates neuronal HMGCR to the acetylcholine system. This analysis provided a model that links neuronal HMGCR to acetylcholine signaling in neuromuscular junctions. Thus, in the third part of this study I measured RNA expression of three key genes in this model – Neurexin1 (Nrx-1), kuzbanian (kuz) and Kuzbanian-like (Kul). Although the results didn’t confirm the expectations about this model, they gave projections to what should be further investigated. |
