Stress/Glucocorticoid Mechanisms in Parkinsonian Pathologies
Abstract
According to the Michael J. Fox Foundation and others, Parkinson s disease (PD) is the fastest-growing neurological disorder in the world. Developing a disease-modifying treatment to slow or halt the unrelenting progression of the disorder is of paramount importance. Prolonged exposure to physiological and/or mental stress is a likely environmental risk factor for manifestation and progression of Parkinson s. We have shown previously that exposure to chronic unpredictable stress enhances the degeneration of susceptible midbrain dopamine cells and worsens PD-related motor behavior in a neurotoxin model of PD, indicating a link between prolonged stress and dopamine cell death. We now propose to determine if stress hormones called glucocorticoids mediate these deleterious actions through its receptor (the glucocorticoid receptor, GR) present on dopamine cells. We will use specialized animal models that are engineered to allow deletion of GR in midbrain dopamine neurons to test whether the absence of GR affords protection from chronic stress-induced exacerbation of aberrant motor and non-motor symptoms and neuropathology in PD-related circuits in the brain. A key pathological hallmark of PD is aggregation of the protein alpha-synuclein (aSyn), which leads to the death of neurons in various regions of the brain that regulate motor and non-motor functions, particularly midbrain dopamine cells. We will also use a state-of-the-art PD model that better mimics the human condition by reproducing some of these pathological features including the seeding and spread of toxic aSyn in dopamine-related pathways that lead to motor and non-motor impairment and, eventually, cell degeneration. We aim to show that eliminating GR in dopamine cells will also prevent or reverse aSyn neuropathology in the brain. This proposal was prepared in response to the FY20 NETP Focus Areas: Basic biology of non-motor symptoms that could lead to the development of new treatments for Parkinson s disease following neurotoxin exposure and System-level mechanism of dopamine refractory motor symptoms in Parkinson s disease, including postural instability, freezing of gait, and treatment-associated dystonia, that could lead to development of new treatments in patients… We also focus on the recommended subtopics of PD-related cognition, psychiatric dysfunction, circuitry, and pathophysiology. Given our background and expertise, our proposal focuses primarily on the pathological role of GR in cognitive and other non-motor and motor symptoms exacerbated by environmental stress exposure. The proposed research will help many persons diagnosed with idiopathic Parkinson s disease, but, in particular, those subpopulations of patients with elevated levels of the stress hormone cortisol due to, for example, a chronic state of stress. Dysfunction of the stress response system is seen in subsets of patients in the clinic and may also affect those with current life stress, both of which can result in greater disability and faster progression of the disease. If the present studies prove fruitful, the potential clinical applications include treatment with approved drugs that block cortisol from binding to its receptor whereby it produces its effects. The development of next-generation GR antagonists, with more specificity and fewer side-effects, is also on the horizon and could even be useful as a Parkinson s disease therapeutic. Potential risks may include the fact that GR receptors are found throughout the body and, thus, drugs that are intended to treat Parkinson s stress-related dysfunction may have unintended side-effects. Such issues may be overcome by targeting the GR-blocking drugs to specifically the midbrain dopamine cells, a subject of future research efforts that may involve gene therapy or other novel approaches to treatment. The projected time it may take to achieve a patient-related outcome is uncertain but likely to be several years away
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110877
Entities
People
- Kim Seroogy
Organizations
- United States Army
- University of Cincinnati