The Role of SATB1 in Neuronal Plasticity and Its Upstream Regulatory Pathway in Parkinson s Disease
Abstract
With more than 17,000 reported cases in 2016, traumatic brain injury (TBI) is one of the most common injuries in the U.S. Armed Forces. It has recently been reported that TBI may be associated with later development of Parkinson s disease (PD). The brain has an intrinsic capability to recover from TBI. This ability of the brain to make adaptive changes on both a structural and functional level is called neuroplasticity. The neuroplasticity of nerve cells enables these cells to extend their nerve fibers, form new contacts between each other and make new network connections within the brain. Defects in neuroplasticity reduce the ability of the brain to recover and can lead to the death of nerve cells, which can result in neurodegenerative diseases such as PD. In a previous study, we discovered that SATB1, a cellular factor involved in gene regulation, has a protective function in the specific nerve cells that die in PD patients. Based on work in a rat model of TBI, it has been reported that SATB1 levels are significantly downregulated after brain injury. Interestingly, it has also been found that SATB1 regulates many genes that are crucial for neuroplasticity. Here, we propose to investigate the interconnection between TBI, neuroplasticity, PD, and SATB1. Hence, this proposal focuses on the FY17 PRP Investigator-Initiated Research Award Focus Area "Mechanisms of neuroplasticity in the Parkinson s disease brain." Based on our preliminary data, we hypothesize that the SATB1 molecule can be activated and inactivated by the addition of endogenous chemical modifications within the nerve cell. These modifications could be used to experimentally switch SATB1 "on" and "off". We aim to identify the specific modification that activates SATB1. We will use high-throughput screening methods to identify small chemical compounds that increase the activity of SATB1. The identified compounds will then be tested in highly specific human stem cell-derived nerve cells with and without PD. We will make use of high-end microscope techniques to monitor the impact of the compounds on nerve cell neuroplasticity and evaluate their potential neuroprotection in PD. In summary, we aim to unravel the mode of activation of the regulatory factor SATB1. The identification and characterization of the pathway that activates SATB1 will lead to the discovery of small compounds that positively modulate neuroplasticity via SATB1 activity. Understanding how the neuroprotective genetic master regulator SATB1 acts will open the possibility of a novel therapeutic approach for patients who suffer from TBI and potentially for PD patients. The identification of compounds that activate SATB1 will help to develop neuroprotective drugs for PD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810467
Entities
People
- Paul Greengard
Organizations
- The Rockefeller University
- United States Army