Alcantara, E. | bioRxiv Science

bioRxiv2024

Investigating the Role of Glyoxalase 1 as a Therapeutic Target for Cocaine and Oxycodone Use Disorder

Methylglyoxal (MG) is an endogenously produced non-enzymatic side product of glycolysis that acts as a partial agonist at GABAA receptors. MG that is metabolized by the enzyme glyoxalase-1 (GLO1). Inhibition of GLO1 increases methylglyoxal levels, and has been shown to modulate various behaviors, including decreasing seeking of cocaine-paired cues and ethanol consumption. The goal of these studies was to determine if GLO1 inhibition could alter cocaine-or oxycodone-induced locomotor activation and/or conditioned place preference (CPP) to cocaine or oxycodone. We used both pharmacological and genetic manipulations of GLO1 to address this question. Administration of the GLO1 inhibitor s-bromobenzylglutathione cyclopentyl diester (pBBG) did not alter the locomotor response to cocaine or oxycodone. Additionally, pBBG had no significant effect on place preference for cocaine or oxycodone. Genetic knockdown of Glo1, which is conceptually similar to pharmacological inhibition, did not have any significant effects on cocaine place preference, nor did Glo1 overexpression affect locomotor response to cocaine. In summary, our results show that neither pharmacological nor genetic manipulations of GLO1 influence locomotor response or CPP to cocaine or oxycodone.

neuroscience↗

bioRxiv2020

Transposable element mobilization in interspecific yeast hybrids

Barbara McClintock first hypothesized that interspecific hybridization could provide a "genomic shock" that leads to the mobilization of transposable elements. This hypothesis is based on the idea that regulation of transposable element movement is potentially disrupted in hybrids. However, the handful of studies testing this hypothesis have yielded mixed results. Here, we set out to identify if hybridization can increase transposition rate and facilitate colonization of transposable elements in Saccharomyces cerevisiae x Saccharomyces uvarum interspecific yeast hybrids. S. cerevisiae have a small number of active long terminal repeat (LTR) retrotransposons (Ty elements), while their distant relative S. uvarum have lost the Ty elements active in S. cerevisiae. While the regulation system of Ty elements is known in S. cerevisiae, it is unclear how Ty elements are regulated in other Saccharomyces species, and what mechanisms contributed to the loss of most classes of Ty elements in S. uvarum. Therefore, we first assessed whether transposable elements could insert in the S. uvarum sub-genome of a S. cerevisiae x S. uvarum hybrid. We induced transposition to occur in these hybrids and developed a sequencing technique to show that Ty elements insert readily and non-randomly in the S. uvarum genome. We then used an in vivo reporter construct to directly measure transposition rate in hybrids, demonstrating that hybridization itself does not alter rate of mobilization. However, we surprisingly show that species-specific mitochondrial inheritance can change transposition rate by an order of magnitude. Overall, our results provide evidence that hybridization can facilitate the introduction of transposable elements across species boundaries and alter transposition via mitochondrial transmission, but that this does not lead to unrestrained proliferation of transposable elements suggested by the genomic shock theory.

genetics↗