Heterogeneity of Parkinson s Disease Patients: Identification and Characterization of Neuroprotective Factors of Early Dopaminergic Neuron Degeneration
Abstract
Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder after Alzheimer’s disease. The prevalence in industrialized countries is estimated to be about 0.3% of the general population and almost 2% among individuals 65 years of age and older. Due to their service, Veterans are believed to be at an increased risk to develop PD. Exposure to pesticides or herbicides is suggested to be one cause of PD. In combat settings, pesticides are commonly used to control insects and plant overgrowth in addition to its tactical use. Interestingly, most people who develop PD were never exposed to high levels of pesticides or herbicides and not all people who were exposed develop PD. This observation strongly suggests an inter-individual susceptibility to PD, which is most likely explained by differences in the genetic background of each individual person. The characteristic motor signs of PD patients are caused by the loss of a specific subtype of nerve cells in a defined area in the midbrain, the so-called dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Interestingly, DA neurons in another region of the midbrain are mainly not affected during the course of the disease. Recently, we compared the two different nerve cell populations in a PD mouse model and identified 19 so-called genetic master regulators that can protect the neurons from cell death. Master regulators are known to be capable of regulating the activity of many different genes. We have found that the activity of some of these master regulators is reduced in human PD patients. In a preliminary experimental approach, we have investigated the molecular function of the first master regulator. Most interestingly, when we genetically activated this master regulator in human PD nerve cell cultures, we were able to protect the cells from death. Based on our highly promising preliminary results, we propose to characterize the cellular function of the remaining 18 master regulators. This will lead to the discovery of novel cellular pathways that can protect the target tissue in PD, the DA neurons, from cell death. To do this, we will (1) genetically modify human DA nerve cells (with and without PD) in culture to identify the mode of action of the master regulator; (2) test the neuroprotective effect in both genetic and toxin-induced mouse models for PD; and (3) generate pharmacologically active compounds that are capable of activating the neuroprotective master regulators. With this knowledge, we will be able to develop drugs that potentially could be used in neuroprotective therapies for incipient PD to prevent early DA neuron degeneration in both familial and environmentally caused PD. To summarize, in this proposal we aim to determine the underlying reasons why specific community-based populations display different grades of severity and disease progression and to understand how neuronal master regulators exert a neuroprotective effect on DA neurons. Understanding how neuroprotective genetic master regulators act will not only help to explain observed inter-individual heterogeneity but also open the possibility of a novel therapeutic approach for PD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710495
Entities
People
- Paul Greengard
Organizations
- The Rockefeller University
- United States Army