Determinants of Basal Forebrain Cholinergic Neuron Vulnerability in Parkinson s Disease and Lewy Body Dementia
Abstract
Parkinson s disease (PD) poses one of the greatest healthcare challenges of our time. With the aging of the general population, the incidence of PD is expected to rise in coming decades. This wave will create not only a humanitarian crisis, but an unsustainable tax on societal resources. Although there are effective symptomatic therapies for the motor symptoms of PD (at least in the early stages of the disease), there are no effective therapies for the non-motor, cognitive dysfunction, and Lewy body dementia (LBD) that commonly accompany PD. This unmet medical need is identified as one of the Fiscal Year 2019 Parkinson s Research Program Focus Areas - Mechanisms of non-motor symptoms of PD from basic biology to clinical application. This gap in clinical care reflects our poor grasp of disease mechanisms. While there has been considerable progress toward understanding genetic and environmental causes of PD and LBD, it is far from clear why some neurons in the brain succumb and others do not. Understanding the basis for this selective vulnerability could provide the insight needed to develop new, potent therapies for non-motor symptoms in PD. The idea behind this approach is simple. Neurons in the brain differ from one another in the same way as people differ from one another. The brain can be viewed as a society of neurons. Neurons have different "jobs." If we understand how the job a neuron does in the brain contributes to vulnerability, then we might be able to reduce their vulnerability by changing the way they do their job. For example, the realization that inhalation of coal dust increased a miner s risk of lung disease led to the introduction of masks and other forms of respiratory protection that lowered disease incidence. One of the most vulnerable types of neuron in PD, LBD, and Alzheimer s disease (AD) is the basal forebrain cholinergic neuron (BFCN). These neurons have a difficult job. Their primary responsibility is to coordinate the activity of distributed neuronal communities to make sure they work together efficiently. This demands that they be constantly active and to support a long, and highly branched line of communication. When these neurons die, the activity of brain communities is poorly coordinated and many of our higher brain function, like memory and thinking, deteriorate. Yet, we know very little about how these incredibly important neurons go about doing their job. Our primary research goal is to generate a comprehensive description of how BFCNs do their jobs and to identify traits that put them at risk. Based upon our study of other neurons that are lost prematurely in PD, our hypothesis is that there is one trait that underlies their selective vulnerability – they work too hard. BFCNs, like other neurons at risk in PD, appear to be constantly active, working to coordinate neural activity in response to environmental challenges. To stay "vigilant" and sustain their lines of communication, BFCNs appear to be constantly stimulating intracellular power-plants (mitochondria). A by-product of stimulation is a form of pollution (free radicals). Over time, the pollution appears to damage the power-plants themselves and neighboring parts of the neuron, leading ultimately to dysfunction and death. By taking advantage of newly developed technologies, we can closely monitor key aspects of how BFCNs are doing their job and to identify ways we might improve their efficiency and lower their risk. We have three primary goals. The first is to determine what drives the activity of BFCNs. Are they "self-motivated" or are they primarily responding to other parts of the brain community? This will allow us to design strategies for controlling their activity. The second goal is to understand how the activity of BFCNs stimulates their power-plants. Our guess is that BFCNs stimulate their power-plants unnecessarily, in anticipation of need rather than actual need, leading to excessive pollution. The third goal is
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010667
Entities
People
- D. James Surmeier
Organizations
- Northwestern University
- United States Army