Autophagy Induction as a Novel Therapeutic Strategy for TSC-Associated Cognitive and Autistic Social Deficits

All cells including neurons count on mechanisms that regulate the balance between protein synthesis and protein degradation, a process known as protein homeostasis, to maintain a functional pool of proteins that is essential for survival and cellular functions. This process is tightly controlled by the mechanistic target of rapamycin (mTOR), a key molecule that promotes protein synthesis and inhibits autophagy, a lysosomal degradation process that maintains protein quality control via the degradation of cellular proteins and organelles to recycle amino acids. Dysregulation of mTOR has been found to be at the core of the pathophysiology of tuberous sclerosis complex (TSC), in which mutations in either TSC1 or TSC2 gene lead to sustained overactivation of mTOR, and as a consequence, excessive protein synthesis and impaired autophagy.

We have recently identified autophagy as a therapeutic target for TSC-associated social and cognitive impairments. Using a Tsc2+/- mouse model of TSC, we found that mTOR hyperactivation in excitatory neurons led to the development of autistic behaviors, including impaired social interaction and social novelty, largely by inhibiting autophagy. Our unpublished work further supports a causal role for impaired autophagy in hippocampal synaptic dysfunction and cognitive impairment in Tsc2+/- mice. Based on these findings, we hypothesize that activating autophagy will provide a therapeutic approach for TSC-associated social and cognitive impairment.

In this study, we propose to evaluate the safety and efficacy of two pharmacologic agents that are capable of augmenting autophagy in vivo, including metformin, a U.S. Food and Drug Administration (FDA)-approved drug for the treatment of type II diabetes mellitus, and Tat-Beclin 1 (TB1) peptide, a novel cell-permeable autophagy inducer that specifically targets the essential component of the autophagy machinery. We will determine the safety, efficacy, and mechanisms of both agents to induce brain autophagy in vivo in Tsc2+/- mice (Aim 1), and whether metformin and TB1 peptide mitigate synapse pathology (Aim 2) and rescue autism-like social and cognitive deficits in Tsc2+/- mice (Aim 3). To achieve these aims, we will conduct experiments that employ a variety of the most current approaches, including behavioral analysis, electrophysiology, live slice imaging, mouse genetics, histology, molecular cell biology, and biochemistry. Successful completion of the proposed study will provide preclinical evidence for the safety and efficacy of autophagy inducers in TSC. The findings can be rapidly translated into clinical trials to test the safety, doses, and efficacy of autophagy inducers in patients, which will, in the long term, improve the quality of life for patients. More broadly, this therapeutic strategy can be effective for many other neurodevelopmental disorders that feature abnormal mTOR activation, including autism spectrum disorders.