Investigation of the Role of the LC3 Conjugation System in Autophagy for Human Reward System Reactivity

Abstract

ObjectivesThe dopaminergic reward system is involved in the etiology of psychiatric disorders, and autophagy has been suggested to interfere with dopamine release. LC3 conjugation plays a key role in autophagy and comprises modification of autophagy protein LC3 with phosphatidylethanolamine. We investigated whether LC3 conjugation may impact on the strength of activation in key regions of the mesolimbic reward system. MethodsTo test our hypothesis, responses of the reward system to conditioned stimuli were assessed using the desire-reason dilemma(DRD) paradigm, that allows for investigation of reward processing during fMRI. Association of a set of missense variants with reward system responses was analyzed in a sample of 214 participants. ResultsAs a main finding, the gene set was associated with both ventral tegmental area (VTA) and nucleus accumbens (NAc) responses to conditioned reward stimuli (empirical P-value R-VTA: 0.008, R-NAc: 0.009). Strongest missense variants were MAP1LC3B_rs113610787 (P=3.219e-05) for association with response in the L-NAc, and ATG4B_rs143448469 (P=4.366e-05) for the R-NAc. ConclusionsFindings provide evidence that variation of the LC3 conjugation system influences responses of the VTA and NAc to conditioned reward stimuli. Further studies are required to replicate the findings, and to investigate the possible role of LC3 conjugation in psychiatric disorders.