Parkinson’s disease researchers to study brain circuits driving symptoms
Aim to understand disease-induced alterations in brain circuitry to develop better treatments
Northwestern University scientists have received two awards for Parkinson’s disease (PD) research from the ASAP Collaborative Research Network, a program of the Aligning Science Across Parkinson’s (ASAP) initiative implemented with partner The Michael J. Fox Foundation for Parkinson’s Research.
ASAP 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.
A team led by D. James Surmeier, the Nathan Smith Davis Professor and chair of neuroscience at Northwestern University Feinberg School of Medicine, received a $9 million award over three years. He and his collaborators will investigate how the dysfunction of brain circuits begins and then evolves to cause difficulty in moving and sleeping. This will allow earlier diagnosis of Parkinson’s disease and increase the chances of stopping and better treating the disease with pharmacological and genetic therapies once it appears.
His project is titled “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 from Northwestern; Rui Costa at Columbia University; Yang Dan at University of California, Berkeley; Silvia Arber at University of Basel; and Jun Ding at Stanford University.
Another ASAP-funded team, led by Rajeshwar Awatramani, professor of neurology at Feinberg, received a $8.9 million award over three years to study dopamine-producing neurons in a brain area called the substantia nigra pars compacta. He and collaborators will investigate how these neurons contribute to movement and how they are affected in Parkinson’s disease.
His project is titled “Redefining PD pathophysiology mechanisms in the context of heterogeneous substantia nigra neuron subtypes.” His core team includes professors at Northwestern Loukia Parisiadou, Daniel Dombeck, Mark Bevan, and Surmeier, as well as Tom Hnasko 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,” said Dr. Eric G. Neilson, vice president for medical affairs and Lewis Landsberg Dean at Northwestern. “These grants recognize the outstanding work being done across many unique spaces to advance our understanding of Parkinson’s disease.”
Northwestern scientists discuss their research projects for these awards:
Developing new therapies to alleviate symptoms
“Identifying the deficits in brain function that are happening early in Parkinson’s disease should help us develop assays that will lead to earlier clinical diagnosis. Earlier clinical diagnosis will maximize the impact of disease-modifying therapies. There currently are none that are proven to work in later stage Parkinson’s disease,” said D. James Surmeier.
“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 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.
“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 slow or stop progression, significantly prolonging the period of time in which current symptomatic therapies are effective.”
Identifying which dopamine neuron subtypes degenerate and which circuits are dysregulated
“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 PD, remains unknown,” said Rajeshwar Awatramani.
“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.
“Our work will identify which dopamine neuron subtypes degenerate and which circuits are dysregulated. 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.”