Monday, May 13, 2024
5/13/2024
A pervasive, persistent challenge faced by traumatic brain injury (TBI) survivors is a significant disturbance in cognition across the spectrum of injury severity. Normal complex cognitive processes require optimal functioning of neuronal networks. When the brain undergoes stress (e.g., ischemia, Alzheimer’s related neurodegeneration, TBI), heat shock proteins (HSPs) are induced to assist in protein folding, degradation and other functions. HSPs, also called chaperones, function to maintain cellular proteostasis through dynamic protein complexes called chaperomes to aid in protein folding, activation, degradation or disaggregation, molecular chaperoning and translocation in normal cells. These interactions aren’t based on monomeric protein expression, but rather through the strength and number of interactions. Under conditions of cellular stress, the chaperomes become biochemically ‘rewired’ to form a network of pathologically stable, high-molecular-weight complexes, recently called the epichaperome. As critical hub proteins, heat shock protein 90 (HSP90) and heat-shock cognate 70 (HSC70) are the central proteins involved in the pathological formation of the epichaperome and are linked together by HSP-organizing protein (HOP). Once HSP90 and HSC70 are biochemically altered into the epichaperome epicenter, importantly, these proteins both lose their normal physiological function of proper protein production and also recruit a wide range of co-chaperones into the scaffold, perpetuating pathological progression. It has recently been demonstrated in Alzheimer’s Disease and in various cancer models that the epichaperome is responsible for the disturbance of protein-protein interaction networks, which ultimately become dysfunctional and drive the pathological phenotype of the disease. It is currently unknown if TBI results in the formation of epichaperome responses. Our preliminary data demonstrate that there is significantly increased high molecular weight expression of HSP-90 and HSC-70, indicative of increased assembly of the maladaptive epichaperome complex, in male and female rats at both acute and sub-acute time-points after controlled cortical impact (CCI). These epichaperome-mediated protein network changes have been identified and therapeutically targeted. PU-AD is an oral, brain-permeable epichaperome inhibitor, which targets the slow kinetics of HSP90 specifically within the epichaperome without altering monomeric HSP90 protein expression and normal function. Preliminary data indicate that systemic administration of PU-AD attenuates cognitive deficits after CCI. The overall goal of the project is to provide proof-of-principle that TBI produces an epichaperome response and that disassembling the epichaperome via PU-AD improves learning and memory. The first aim will provide a comprehensive assessment of key chaperome components that participate in the formation of the epichaperome after TBI across brain regions and time-points. The second aim will evaluate a dose response and treatment window of PU-AD in TBI looking at epichaperome and neurobehavioral outcomes. Since PU-AD is approved for clinical trial for AD, a pathway for clinical translation exists for TBI.
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