Sortwell Lab

 

About the Sortwell Lab

Insert summary of Sortwell Lab and key research areas.

Lab Personnel

Caryl E. Sortwell, PhD, Primary Investigator

Christopher J. Kemp

Joe Patterson, PhD

Jacob Howe

Michael Kubik

Anna Stoll

 

Synucleinopathy

Parkinson’s disease (PD) is characterized by the accumulation of clumps of a protein called alpha-synuclein within neurons in areas of the brain that become dysfunctional and can eventually degenerate. Understanding the role of this synucleinopathy – what pathological processes are associated with it and whether alpha-synuclein inclusions are protective or toxic or merely bystanders – is critical to treating both the symptoms of PD and slowing neurodegeneration. Our lab uses an animal model system in which alpha-synuclein inclusions are triggered to form to study the impact of these inclusions on neuron survival, trophic factor signaling, dopamine transmission, neuroinflammation and motor function. In collaboration with Dr. Joe Patterson, we analyze the genetic consequences of the formation of alpha-synuclein inclusions. Our in vivo synucleinopathy platform, called the alpha-synuclein preformed fibril model, is being used with increasing frequency in PD research around the world. We leverage scientific methodologies developed in our laboratory as well the expertise of collaborators to carefully examine the pathophysiological events associated with synucleinopathy. Where possible, we directly compare the effects we observe in our alpha-synuclein fibril model to the parkinsonian brain. We put special emphasis on characterizing the time course and magnitude of these effects. The overall goal of this project is to deepen our understanding of the effects of synucleinopathy as well as to inform the experimental design of future symptomatic and neuroprotective approaches.

 

 

Neuroprotection 

Parkinson’s disease is defined by protracted degeneration of neurons, specifically neurons of the nigrostriatal system that are the source of the neurotransmitter dopamine. Loss of dopamine in the striatum results in movement dysfunction. Numerous pharmacotherapies that increase dopaminergic transmission are available to treat PD motor symptoms, however as neurons continue to degenerate these treatments lose their efficacy. Therefore, the ability to slow or halt the continuing loss of neurons in PD would provide patients with the ability to manage their symptoms and improve their quality of life. Using the alpha-synuclein preformed fibril model we test the ability of a variety of therapies to decrease the accumulation of alpha-synuclein inclusions, protect nigrostriatal dopamine neurons, maintain dopaminergic function and attenuate synuclein inclusion-triggered neuroinflammation. These therapeutic approaches range from novel or repurposed drug therapies to exercise to the surgical therapy of deep brain stimulation. The overall goal of this project is to identify approaches with the greatest likelihood to slow the progression of PD and to provide scientific evidence to support clinical trials of disease-modifying therapies.

Precision Medicine 

Precision medicine is an approach that seeks to identify the best therapy for a specific patient based on their individual genome. Almost all patients with PD ultimately are treated with the drug levodopa (Sinemet) to increase dopaminergic transmission to alleviate motor dysfunction. However, patient response to levodopa is quite heterogeneous with some patients experiencing excellent symptomatic relief while other patients see only modest symptom improvement. In addition, increasingly more PD patients are turning to the neurosurgical therapy of deep brain stimulation (DBS) to treat their parkinsonian symptoms. As with levodopa therapy, not all patients experience the same level of symptom improvement when treated with DBS. Based on previous laboratory research we have evidence to suggest that a specific neurotrophic factor called brain-derived neurotrophic factor (BDNF) is involved with the efficacy of both levodopa and DBS. BDNF is a naturally occurring protein in the brain that plays critical roles in maintaining the health and function of neurons. In the human genome there is a variant of the BDNF gene (rs6265) that is quite common, 1 out of every 3 people possesses a form of the BDNF gene that results in deficits in BDNF release in the brain. In this project we use BDNF genetic information from PD patients and analyze their response to levodopa or DBS to determine whether a particular treatment approach is best able to improve PD symptoms. The overall goal of this project is to determine whether BDNF genotyping at the time of PD diagnosis can be used to inform the therapeutic decisions made by patients and their doctors to optimize relief from parkinsonian symptoms.