Targeted Protein Relocalization to Enhance Neuronal Resilience and Regeneration

As lifespans increase, preserving brain health into old age is increasingly critical. Neurodegenerative diseases like Lou Gehrig’s and Alzheimer’s remain amongst the hardest to treat with limited therapies, necessitating new methods to understand and target their root causes. An emerging insight is that a protein’s location within a neuron greatly affects its function. Proteins in the wrong location lose proper activity and can adopt harmful functions. Such protein mislocalization is a common feature in many neurodegenerative diseases. To correct this, we use specially designed drug-like molecules (TRAMs-Targeted Protein Relocalization Molecules) to guide misplaced proteins back to their proper cellular location by pairing them with resident “shuttle” proteins in the intended location. We will apply TRAMs in patient stem cell-derived neurons, tracking subsequent protein behavior and cell health changes using advanced imaging and assays to determine if mislocalized proteins are a cause or symptom of disease. If uncovered to be the root cause of neurodegenerative disease, we will conduct high-throughput screens to discover TRAMs that directly engage the mislocalized target protein with the appropriate shuttle protein identified in our mechanistic studies, enabling novel treatments. In parallel, to test protein relocalization directly in models of disease without requiring prior genetic engineering, we will develop protein-based TRAMs using computational design. These can be developed as gene therapies against intractable diseases and enable target validation to drive drug screens. Protein relocalization enables the control of multitasking proteins harboring location-dependent functions - a property inaccessible to traditional drugs. We also seek to utilize a combination of genetic engineering and TRAMs to explore the relocalization of a key neuronal health related protein and its downstream effects on neuronal regeneration and longevity. By blending biology, chemistry, and neuroscience, we explore an entirely new way to protect brain cells in disease and promote their longevity in healthy states.