ROLE OF LSD1 IN AGING- AND STRESS- DEPENDENT EPIGENETIC DRIFT LEADING TO DEPRESSION AND ANXIETY DISORDERS

The current understanding of the pathophysiologic processes underlying neuropsychiatric disorders remains dramatically limited, despite their epidemic diffusion and tremendous impact on patients’ health and society. Mounting evidence suggests that the disruption of stress-coping mechanisms might be coupled to maladaptive forms of plasticity underlying stress-vulnerability, fostering mood disorders such as anxiety and major depressive disorder (MDD). The correct tuning of the relative ratio between the epigenetic enzyme Lysine-Specific Demethylase 1 (LSD1) and its neuronal-specific dominant negative isoform neuroLSD1 is crucial to guarantee homeostatic adaptive plasticity in response to environmental stimuli, in the frame of a stress-resiliency instrumental pathway. Another homeostatic regulator of excitatory neurons playing a fundamental part in environmental stress-response is the neuronal-enriched splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) that is heavily implicated in the onset of several neurological disorders, such as autism and epilepsy, and has been recently listed among the few genetic loci associated to MDD. During my PhD, I dissected a higher primates-restricted functional interaction between RBFOX1 and LSD1. Specifically, RBFOX1, thanks to a single nucleotide variation present only in higher primates and humans and generating a new acceptor splice site, acquires the ability to regulate splicing inclusion of a novel LSD1 cryptic exon, that we named exon E8b. This alternative spliced exon not only negatively regulates LSD1 levels by Nonsense-mediated mRNA decay, but also modulates brain-restricted expression of neuroLSD1, affecting LSD1 and neuroLSD1 ratio. Notably, we further demonstrated the involvement of LSD1/neuroLSD1 ratio modulation in physiological brain aging and psychiatric drift in humans. If on the one hand the evolution-driven acquisition of LSD1 as RBFOX1-regulated target could contribute to increase the complexity of stress response and environmental adaptation, on the other hand it likely represents a novel vulnerability harbor multiplying susceptibility substrates for stress-related neuropsychiatric disorder. In parallel, always with the idea to identify neurobiological mechanisms associated with stress susceptibility, I evaluated the involvement of specific LSD1 genetic variants able to set different levels of LSD1/neuroLSD1 ratio and potentially impacting stress susceptibility in humans.