THE ROLE OF PARKIN IN THE NEUROPATHOLOGY OF TBI

Traumatic brain injury (TBI) results in significant damage and degeneration. The ability to preserve cellular integrity immediately after TBI represents a valuable therapeutic target. The body has developed mechanisms for clearing cells of their damaged organelles and cellular waste, and hence rescuing the cell from death. Neurons, due to their long post-mitotic neuronal life and large cytoplasmic volume, are heavily reliant on these autophagic mechanisms for maintaining cellular integrity and homeostasis. Parkin, is a multi- functional protein that has a significant role in removal of damaged proteins and organelles from the cell. Mutations in the gene encoding Parkin, PARK2 are responsible for the majority of autosomal recessive forms of Parkinson’s disease. Parkin has neuroprotective ability in many different neuronal stress models and in animal models of Parkinson’s disease, but the exact mechanism through which it acts as a neuroprotective protein in different scenarios is not clear. Additionally reduction or overexpression of Parkin in vitro and in vivo has shown that Parkin is intimately involved in clearing proteins such as Tau, alpha-synuclein, TDP-43 and beta-amyloid that are associated with the development of neurodegenerative diseases. Despite its importance in models of neurodegenerative disease, there is nothing known about the role of Parkin after TBI. We have found that Parkin is induced in neurons after both controlled cortical impact injury and blast overpressure injury. Further we have evidence that in Parkin null mice, the absence of Parkin leads to deficiencies in clearing of phospho-Tau from the cell. We hypothesize that Parkin is neuroprotective after TBI, in part by promoting clearance of intraneuronal proteins and damaged organelles that build up in response to injury. We propose to examine parkin’s role in different models of TBI to determine whether Parkin alters the response to TBI. In this proposal we will use Parkin null and wild type mice together with autophagy reporter mice to examine the effect of Parkin absence on autophagic processes, as well as the general recovery from injury. We therefore propose 1) To characterize and compare the role of Parkin in the response of the mouse brain to each of three different injury models, controlled cortical impact (CCI) injury, closed head impact (CHI) injury and blast overpressure (BOP) injury; 2) To determine whether the presence or absence of Parkin alters autophagic mechanisms after either CCI, CHI or BOP injury and 3) To determine whether stimulation of Parkin function by treatment with the FDA approved Abl tyrosine kinase inhibitor, nilotinib, at different time points after injury, promotes recovery and/or enhances autophagy after CCI. Understanding Parkin function after TBI should open several new lines of investigation to enhance recovery from injury.