Director: D. James Surmeier, Ph.D.
Title: Rhythmicity and Synchrony in the Basal Ganglia
Budget End Date: 7/31/2018
The Northwestern University Center is focused on two major lines of study in Parkinson’s disease (PD) with strong translational potential. The first 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 and will attempt to translate these discoveries into new therapeutic approaches for late-stage PD patients.
The second line of study in our Center builds upon recent insights gained into the factors underlying vulnerability of dopaminergic neurons in the substantia nigra pars compacta (SNc) that are lost in PD. These studies suggest that the engagement of voltage-gated calcium channels during autonomous pacemaking helps to create a basal mitochondrial stress in SNc dopaminergic neurons, making them vulnerable to genetic mutations and environmental toxins. Other types of neuron that display vulnerability in PD, like neurons in the locus coeruleus and dorsal motor nucleus of the vagus appear to have a similar physiological phenotype, replete with basal mitochondrial oxidant stress. Importantly, these studies also suggest this vulnerability can be diminished with a drug that is approved for human use, an inference supported by a number of recent epidemiological studies. A Phase II human clinical trial with the dihydropyridine isradipine has been completed and an NINDS-supported Phase III clinical trial with early stage PD patients began in 2014. In addition, our Center initiated efforts to identify new and more powerful disease modifying drugs. Selective antagonists of Cav1.3 channels that lack the cardiovascular side-effects of dihydropyridines are now in pre-clinical development.
The Northwestern University Udall Center brings together four principal investigators (PIs) from two research institutions (Northwestern University and University of Texas) with complementary expertise. The Center is directed by Dr. D. James Surmeier (Northwestern University). Project leaders are Drs. Surmeier, Mark Bevan (Northwestern University), Savio Chan (Northwestern University) and Charles Wilson (University of Texas, San Antonio). In addition to these research teams, the Center has an Administrative Core to coordinate activities of the projects and a Molecular Core to serve the genetic profiling and gene therapy aims of the projects.
The above studies address the following NINDS PD2014 research priorities:
*will be made available through Addgene
Cooper G., Lasser-Katz E., Simchovitz A., Sharon R., Soreq H., Surmeier D.J., Goldberg J.A. Functional segregation of voltage-activated calcium channels in motoneurons of the dorsal motor nucleus of the vagus. J Neurophysiology, 2015. 114(3): 1513-20. PMCID: PMC4561632 [Available on 2016-09-01].
Hernández VM, Hegeman DJ, Cui Q, Kelver DA, Fiske MP, Glajch KE, Huang TY, Justice NJ, Chan CS. Paravalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus. J Neurosci, 2015, 35(34):11830 –11847. PMCID: PMC4549397 [Available on 2016-02-26].
Chu HY, Atherton JF, Wokosin D, Surmeier DJ, Bevan MD. Heterosynaptic regulation of external globus pallidus inputs to the subthalamic nucleus by the motor cortex. Neuron, 2015, 85: 364-76. PMCID: PMC4304914.
Wilson CJ. Oscillators and Oscillations in the Basal Ganglia. Neuroscientist, 2014, pii: 1073858414560826. [Epub ahead of print]. PMCID: PMC4454624 [Available on 2016-06-01].
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.
Last Modified March 8, 2016