Talene Yacoubian, MD, PhD

Name of Institution:

University of Alabama at Birmingham, AL

Project Title:

Rab27b as a Potential Regulator of Alpha-Synuclein Spread.

Investigator:

Talene Yacoubian, MD, PhD


Dr. Yacoubian is an Associate Professor of Neurology and Parkinson Association of Alabama Scholar in Parkinson’s Research in the Division of Movement Disorders and Center for Neurodegeneration and Experimental Therapeutics. Dr. Yacoubian received her undergraduate degree from Harvard University and her MD and PhD degrees from Duke University School of Medicine. She completed her Neurology Residency at Massachusetts General Hospital/Brigham & Women’s Hospital. Prior to joining the UAB Neurology faculty, Dr. Yacoubian was a Research and Clinical Fellow in Movement Disorders at Harvard Medical School/Massachusetts General Hospital. She currently divides her time between patient care and laboratory research focused on Parkinson’s disease. Dr. Yacoubian’s lab is focused on understanding the pathophysiology of Parkinson’s disease with the long-term goal of developing neuroprotective therapies.

Research Objectives and Relevance to Diagnosis/Treatment of PD:

The goal of this project is to test whether Rab27b regulates the cell-to-cell spread and toxicity of alpha-synuclein, a key protein implicated in the neurodegenerative process in Parkinson’s disease (PD).

Development of effective therapies in PD depends on a clear understanding of the mechanisms underlying the loss of brain cells in PD, yet those mechanisms are poorly understood. One key protein that is central to PD is alpha-synuclein (α-synuclein).  Recent evidence suggests that α-synuclein can act like a “prion” protein: brain cells release aggregated α-synuclein, and this extracellular α-synuclein then causes misfolding and aggregation of α-synuclein in neighboring brain cells, thereby injuring the neighboring cells. Rab27b is a protein that can regulate protein secretion in the brain. We recently observed a twofold increase in Rab27b levels in cells that expressed high levels of α-synuclein and in human PD brains. We hypothesize that under conditions of elevated α-synuclein levels, neurons upregulate Rab27b expression to promote α-synuclein release from cells in an attempt to maintain cell homeostasis. Yet, such release could inadvertently promote a-synuclein transmission.

We will test the impact of Rab27b in two models of α-synuclein spread: 1) a paracrine α-synuclein model, and 2) an in vitro fibril model. We will use knockdown and dominant negative methodology to test if Rab27b affects α-synuclein release, aggregation, and toxicity in these models.

If we show that Rab27b regulates the spread and toxicity of α-synuclein, then our studies will point to Rab27b as a potential target for therapeutics in PD.

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