Mechanisms Underlying Sleep Disturbances in Parkinson s Disease
Abstract
Our proposed work addresses the FY20 Neurotoxin Exposure Treatment Parkinson s Focus Area of Basic biology of non-motor symptoms that could lead to the development of new treatments for Parkinson s disease following neurotoxin exposure. Specifically, the proposed project focuses on the basic biology of disrupted sleep, one of the most common yet poorly understood non-motor symptoms of Parkinson s disease (PD). It has been estimated that 50%-90% of PD patients suffer from at least one form of sleep disturbance. In addition to being a major contributor to the declined quality of life in PD patients, disrupted sleep emerges well before the onset of motor symptoms and is considered a risk and progression factor of PD. However, mechanisms underlying these sleep disturbances remain largely unclear, hindering the development of specific treatments that alleviate PD-associated sleep disturbances. Indeed, many aspects of sleep disturbances in PD patients are not sufficiently managed and some can even be exacerbated by commonly used PD treatments. At the forefront of the challenge to the understanding and treatment of PD-associated sleep problems is the lack of valid translational animal models. Previous rodent models fail to capture the constellation of the most prominent features of disrupted sleep in PD, including insomnia, fragmented sleep, and excessive daytime sleepiness. The lack of promising animal models has been preventing comprehensive investigations of the pathophysiology underlying sleep disturbances in PD and preclinical tests of potential therapeutics. To address this challenge, we studied a new mouse model of PD, referred to as the MCI-Park model, in which mitochondrial complex I (MCI) function is selectively abolished in dopaminergic neurons, mimicking the key pathogenic feature of neurotoxin-related PD. In addition to progressive PD-like neuropathology and motor deficits, this mouse model displays profound and progressive sleep disturbances with striking resemblances to multiple predominant features of sleep disturbances observed in PD patients. The set of sleep disturbances captured in this model is more complete than any other rodent models. With this unique model, we are now in an unprecedented position to investigate the mechanisms and treatments of sleep disturbances in PD, particularly in relation to neurotoxin exposure. Previous studies suggest that many basal ganglia neural circuits involved in regulating motor functions also regulate sleep. In PD, functions of these circuits are perturbed at the circuitry, cell function, and molecular network levels. Therefore, we will focus our proposed studies to determine the molecular, cellular, and circuitry mechanisms in these networks of neurons that are particularly relevant to PD and regulation of sleep, using advanced genetic, molecular, and physiological approaches in the MCI-Park mice. We will also test whether commonly used PD treatments and sleep aids alleviate sleep disturbances in the MCI-Park mice and whether treatments targeting sleep can be used to delay the progression of PD and to attenuate PD symptoms. The ultimate goal of our research is to enable new treatments of PD. Given the prevalence of sleep problems in PD patients, our research is expected to have a significant and widespread impact on the PD community. Since our mouse model focuses on MCI dysfunction, the common pathogenic feature of neurotoxin-related PD, our research is particularly important for developing new treatments for PD caused by risk factors associated with military deployment and environmental and/or occupational exposures. MCI dysfunction is also associated with sporadic and many familial forms of PD, and thus our research is also expected to impact the broad PD community. Mechanisms underlying sleep disturbances discovered in our proposed studies will immediately enable the development of new PD treatments targeting these mechanisms. Results from our
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110749
Entities
People
- D. James Surmeier
Organizations
- Northwestern University
- United States Army