Udall Center - Northwestern University

 

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Director: D. James Surmeier, Ph.D.

Title: Rhythmicity and Synchrony in the Basal Ganglia

Website: http://physio.northwestern.edu/research/udall/index.html


Central Theme

Our Center is focused on two major lines of study in Parkinson’s disease (PD) research with strong translational potential. The first line of study focuses on the mechanisms underlying the pathological rhythmic bursting activity patterns in the basal ganglia network formed by the subthalamic nucleus (STN), the external segment of the globus pallidus (GP) and the substantia nigra pars reticulate (SNr). This activity is thought to be responsible for the motor symptoms of PD. Our group has identified adaptations in the STN-GP-SNr network in PD models that could be responsible for this pathophysiology. Our research teams are pursuing these discoveries and will attempt to translate it into new therapeutic approaches for late stage PD patients.

Our center also is focused on the causes of PD in the hope of developing disease modifying therapies. This effort has focused on the factors underlying selective vulnerability of dopaminergic neurons in the substantia nigra pars compacta (SNc), whose death in PD is responsible for bradykinesia and rigidity. These studies led to the recognition that autonomous activity and the engagement of voltage-gated calcium channels created a basal mitochondrial stress in at-risk SNc dopaminergic neurons, increasing their vulnerability to genetic mutations and environmental toxins. Importantly, these studies also suggest that vulnerability can be diminished with a drug that is approved for human use, an inference supported by epidemiological studies. These observations led to an NINDS-supported Phase III clinical trial in early stage PD patients with the drug isradipine that will be completed in 2018. While continuing our effort to understand how these intrinsic mechanisms, as well as synaptic mechanisms, contribute to pathogenesis, we have also intiated efforts to identify new and more powerful disease modifying drugs that lack significant side-effects.  More recently, our team has expanded our study of pathogensis to pursue the linkage between psychostimulant use and PD risk.  This effort has uncovered an unexpected connection between mitchondria, calcium and dopamine in the axon terminals of SNc dopaminergic neurons that might drive terminal degenration with prolonged psychostimulant use.  This work also identified a strategy for alleviating degeneration with FDA approved drugs.


Center Structure

The Northwestern University Udall Center brings together four principal investigators from two research institutions (Northwestern University and University of Texas) with complementary expertise. The Center has four research projects and two supportive cores.

Project 1: Determinants of SNc neuron activity and vulnerability in PD models (D. James Surmeier, PhD) examines the role of the pedunculopontine nucleus and nicotine in regulating oxidant stress in substantia nigra dopaminergic neurons.

Project 2: Intrinsic and synaptic determinants of activity in GPe neurons in PD models (C. Savio Chan, PhD) pursues the mechanisms governing the emergence of synchronous rhythmic bursting in globus pallidus neurons in Parkinson’s disease, focusing on a novel class of these neurons that project to the striatum.

Project 3: Intrinsic and synaptic determinants of activity in STN neurons in PD models (Mark Bevan, PhD) explores the role of cortical and pallidal input to the subthalamic nucleus in driving oscillatory behavior in Parkinson’s disease.

Project 4: Desynchronization of basal ganglia neurons by stimulation (Charles Wilson, PhD) explores the mechanisms underlying the symptomatic benefit of deep brain stimulation.

These projects make use of advanced molecular, optogenetic, pharmacogenomic, imaging and electrophysiological approaches to achieve their aims.

The Center is supported by the Administrative Core (Dr. Surmeier) to coordinate activities of the projects and a Molecular Core (Dr. Chan) to serve the genotyping and gene delivery aims of the projects.

 

Public Health Statement

Our Udall Center has two primary goals. The first goal is to gain a better understanding of the causes of PD. Our approach to this difficult problem has been to ask what is different about vulnerable dopaminergic neurons. This led us to the discovery that the engagement of a peculiar type of calcium channel in autonomous pacemaking increased the sensitivity of dopaminergic neurons to mitochondrial toxins used to create models of PD. Subsequently, we have shown that calcium entry through this channel increases mitochondrial oxidative stress and exacerbates the deleterious consequences of at least one genetic mutation associated with familial forms of the disease. The truly exciting thing about this discovery is that this channel is sensitive to an FDA approved class of drugs with an outstanding safety record. Clinical trials are underway in early stage PD patients to determine whether antagonizing this channel slows the progression of the disease. This insight has also spawned a drug discovery effort aimed at identifying new more potent and selective antagonists of this channel. This work has already yielded novel drugs that are in preclinical testing.

The second goal is to understand what happens to the motor circuitry of the brain when dopaminergic neurons are lost to the disease. If we can figure out how the network activity is changed, perhaps we can correct it. Although the problem is complex, this effort has already yielded a major insight into how the aberrant activity thought to be responsible for the inability to move arises. These studies are identifying a number of potential targets for pharmacological or genetic intervention that are currently being tested in animal models. These studies clearly hold the promise of powerful new therapies for late stage PD patients.
 

Budget End Date: 2018/07/31

NIH Grant Number: P50 NS047085