Northwestern University scientists have received two awards totaling nearly $18 million for Parkinson's disease research from The ASAP Collaborative Research Network, a program of the Aligning Science Across Parkinson's (ASAP) initiative being implemented through The Michael J. Fox Foundation.
The ASAP network supports multidisciplinary, multi-institutional research teams to address key knowledge gaps in the basic circuit mechanisms that contribute to the development and progression of Parkinson's disease.
D. James Surmeier, PhD, the chair and Nathan Smith Davis Professor of Neuroscience, received a $9 million award over three years to study "Distributed circuit dysfunction underlying motor and sleep deficits in a progressive mouse model of Parkinson's disease." Surmeier, the principal investigator, will collaborate with Ann Kennedy, PhD, assistant professor of Neuroscience from Northwestern; Rui Costa, DVM, PhD, professor of Neuroscience and Neurology at Columbia University; Yang Dan, PhD, professor of Neurobiology at University of California Berkeley; Silvia Arber, PhD, at University of Basel; and Jun Ding, PhD, associate professor of Neurosurgery and of Neurology at Stanford University.
Rajeshwar Awatramani, PhD, professor of Neurology in the Division of Movement Disorders, received an $8.9 million award over three years to study "Redefining Parkinson’s disease pathophysiology mechanisms in the context of heterogeneous substantia nigra neuron subtypes." His core team includes include Loukia Parisiadou, PhD, assistant professor of Pharmacology; Daniel Dombeck, PhD, associate professor in the Weinberg College of Arts and Sciences, and of Neurology and Neuroscience; Mark Bevan, PhD, professor of Neuroscience; and Surmeier at Northwestern; as well as Thomas Hnasko, PhD, at University of California San Diego.
These two awards, given after a yearlong international competition, are a major coup for the university and the interdisciplinary collaborations fueling our leading-edge discoveries in neuroscience. These grants recognize the outstanding work being done across many unique spaces to advance our understanding of Parkinson's disease."
Eric G. Neilson, MD, vice president for medical affairs and Lewis Landsberg Dean
Scientists discuss their research projects for these awards:
"By aligning alterations in brain activity with behavior as the parkinsonian state evolves, we can determine the roles played by specific circuits in the symptoms of the disease. We also can discern causality. This will allow the development of new targeted therapies for alleviating symptoms.
"For example, in late-stage Parkinson’s disease patients, the standard symptomatic therapy, levodopa, stops being effective because there are too few cells left to convert it to dopamine. These patients have few options at this point. A recent gene therapy trial attempting to elevate expression of the enzyme necessary to convert levodopa to dopamine in the striatum failed apparently because this region was simply too big.
"Study of our new mouse model revealed the loss of dopamine release in the substantia nigra itself was critical to the emergence of motor symptoms. The substantia nigra is much smaller than the striatum and much easier to cover with a gene therapy. Indeed, a single virus injection into the substantia nigra of fully parkinsonian mice significantly increased the ability of levodopa to enable normal movement. This result points to the possibility of a completely novel therapy for late-stage Parkinson’s disease patients.
"By understanding the cascade of events underlying the emergence of clinical Parkinsonism, we may be able to develop new interventions that stop disease progression. It may be that as the disease evolves, before clinical diagnosis, that the activity in brain circuits begins to actually accelerate the loss of dopaminergic neurons. If this is the case, then correcting the activity of these circuits may actually slow or stop progression, significantly prolonging the period of time in which current symptomatic therapies are effective."
"The motor symptoms of Parkinson’s disease result from the degeneration of the dopamine-producing neurons in a brain area called the substantia nigra pars compacta (SNc). Recent findings suggest that the SNc is diverse and is comprised of dopamine neurons with distinct properties. How these dopamine neuron subtypes contribute to movement, and how they are affected in Parkinson’s disease remains unknown.
"Our team aims to provide a detailed understanding of the diverse dopamine neurons in terms of their distinctive molecular signatures, unique connectivity and specific functional contributions to motor behavior. We also want to uncover how these neurons and their circuits are disrupted in mouse models of Parkinson’s disease harboring mutations in the LRRK2 gene, that model one of the most common heritable forms of Parkinson’s disease.
"Our work will identify which dopamine neuron subtypes degenerate and which circuits are dysregulated in Parkinson’s disease. This knowledge will be important for understanding and optimizing therapies, such as deep brain stimulation, that are aimed at restoring normal circuit function. Second, our studies will identify the molecular targets of the hyperactive LRRK2 enzyme, which will be critical for the optimization of LRRK2 inhibitor drugs and their application in patients."
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