Cis proline directed proteotoxicity in the early development and therapy of traumatic brain injury and vascular dementia - Project Summary Early intervention is critical for inhibiting progression of Alzheimer's disease (AD) and related neurodegenerative disorders. Cis phosphorylated Thr231-Pro tau (cis P-tau) has been implicated as an early and pathogenic tau conformation driving neurodegeneration in AD, traumatic brain injury (TBI) and vascular dementia (VaD). In this proposal, I will explore how TBI and cerebral hypoperfusion lead to cis P-tau induction, and how neurons potentially antagonize cis P-tau and other forms of early tau pathology through a mounted transcriptional response in the excitatory neurons. From an unbiased genetic screen, JNK3 has emerged as the first kinase directly phosphorylating cis tau and recognizing the proline in the unusual cis conformation. In addition, single- cell transcriptomic profile and extensive preliminary data consistently support that a REST driven neuronal response may antagonize this cis proline directed proteotoxicity during the prodromal period after brain injuries. The goals of the proposal are to determine the extent to which JNK3 induces cis P-tau and neurodegeneration in TBI/VaD mice and patients (Aim1, K99 phase), to determine if early induced REST inhibits cis P-tau and/or confers neuroprotection in culture, TBI/VaD mice and patients (Aim2, K99+R00 phase) and to evaluate the therapeutic potential of early JNK3 inhibition and rescue of REST expression in the chronic stage in TBI/VaD mice (Aim3, R00 phase). In the mentored K99 phase, the research goal is to determine the extent of JNK3 and REST functions in modulating cis P-tau while receiving training. In R00 phase, the research goal is to unbiasedly and rigorously evaluate the therapeutic potential of modulating cis P-tau by perturbing JNK3 and REST at different stages of TBI and VaD mouse models. The short-term career goal is to receive multidisciplinary training from experts in the field, to complete the proposed studies, to apply for the first NIH R01 grant and to establish a research program to study mechanisms related to the induction and modulation of cis P-tau, a robust, early and druggable driver of neurodegeneration in TBI, VaD and AD. The long-term career goal is to direct a lab to discover and study early mechanisms of onset of age-related neurodegenerative disorders. The training-oriented Yankner lab, multidisciplinary advisory committee team and the highly collaborative and resourceful environment in the Harvard Medical School Department of Genetics offer the diverse technical and professional training in line with this goal.
