Modulation of Autophagy via Camelid Nanobodies Targeting Transmembranous Atg9a to Selectively Shape Stress Resilience

• Applicants: Dr. Nils Gassen; Privatdozent Mathias V. Schmidt, Ph.D.
• Subject Area: Biological Psychiatry ; Biological Psychology and Cognitive Neuroscience ; Cognitive, Systems and Behavioural Neurobiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 542802080

Mental health disorders are extremely prevalent in our society. Not only are they a burden for the affected person, but also for their socio-environment, health care systems and the economy. Current pharmacological and psychological treatments for mental disorders often fall short in their treatment efficacy and are largely still based on trial and error, with an unacceptable proportion of patients continuing to suffer from clinically interfering symptoms despite treatment. Specifically, there is currently no biologically-driven strategy available to health care workers and individuals to proactively increase individual stress resilience and prevent the development of mental illness following stress exposure. Autophagy is an evolutionary conserved cellular housekeeping process implicated in the surveillance and recycling of cellular proteins and organelles, thereby maintaining cellular homeostasis and functioning. Importantly, autophagy has been centrally linked to stress-related disorders and mental health. Consequently, genome-wide and proteome-wide association studies have indicated a significant over-representation of autophagy-related pathways in multiple brain disorders. Despite these promising findings, a comprehensive analysis of the role of autophagy during stress and stress-related mental disorders, and an investigation of autophagy-inducing intervention strategies have not been conducted to date. Based on recent evidence and our own findings, we propose that targeting autophagy activation through transmembrane Atg9a exerts rapid-acting neuronal plasticity and metabolism-improving properties, which might increase resilience to stress-induced phenotypes. To assess the mechanistic, functional and behavioral effects of these Atg9a we will first establish a multilevel toolbox for characterization of Atg9a-driven function. For calibration of our tools, we will use Atg9a loss-of-function and gain-of-function cellular as well as mouse models to determine Atg9a-dependent autophagy. The assays, tailored to assess Atg9a-dependent mechanistic, neuroplasticity and neurometabolism-related outcomes will then be applied to the newly designed highly selective Atg9a-Nanobodies (Atg9a-Nbs). Targeting autophagy activation through Atg9a-Nbs will provide the unique opportunity to dissect Atg9a-mediated effects on autophagy and its impact on stress resilience. To this end, the Gassen and Schmidt labs will join forces and combine their particular expertise in molecular, cellular, metabolic, physiological and behavioral approaches. By unraveling the mechanistic details of Atg9a-dependent autophagy in crosstalk with stress-signaling we aim at paving the way for novel treatment strategies and propose Atg9a-mediated autophagy as novel target for interventions against disorders such as major depression.

• DFG Programme: Research Grants