Unni Lab
Vivek K. Unni
MD, PhD, Columbia University 2003
Faculty Profile
unni@ohsu.edu
503-494-7230
Vivek joined the Department of Neurology and the OHSU Parkinson Center in September 2011. He is now an Associate Professor, Director of the Jungers Center for Neurosciences Research, and the John Hammerstad, MD, Professor of Basic Research of Movement Disorders at OHSU. Vivek received a BS in Chemistry and Biological Sciences from Stanford in 1995. He then earned a MD and PhD from Columbia University in 2003, where his research in Steven Siegelbaum’s lab was on synaptic plasticity in the hippocampus, using multiphoton imaging and whole-cell patch clamp recording methods. After a medical internship at St. Luke’s-Roosevelt Hospital in New York City, he completed a neurology residency and movement disorders fellowship at Massachusetts General Hospital/Brigham & Women’s Hospital. Before joining OHSU, Vivek was an Instructor in Neurology at Harvard Medical School and a research fellow in the laboratories of Bradley Hyman and Pamela McLean at Mass General. During his fellowship, he pioneered the development of approaches to study alpha-synuclein in the living brain of mice using in vivo multiphoton imaging through “cranial windows.”
In his recent work, Vivek is using in vivo multiphoton imaging to examine the aggregation of alpha-synuclein in mouse models of Parkinson’s Disease (PD) and Lewy Body Dementia (LBD), and a variety of techniques to study the novel hypothesis, developed in his lab, that alpha-synuclein plays unexpected roles in the cell nucleus in DNA repair. Below is a 5 minute video by Vivek, produced by the World Parkinson Congress for their 2023 Barcelona meeting, describing what is known about the normal function of alpha-synuclein.
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Research
The Role of Protein Aggregation in Neurologic Disease
Although many neurodegenerative diseases are characterized by the abnormal aggregation and accumulation of specific proteins, the exact protein in each disease varies (e.g. alpha-synuclein in PD and LBD, beta-amyloid and tau in Alzheimer’s Disease, tau and TDP-43 in forms of Fronto-temporal Dementia and Amyotrophic Lateral Sclerosis, huntingtin in Huntington’s Disease, etc.). Of all these diseases, the best evidence that simply increasing the specific protein level can cause disease exists for PD and LBD. One strong piece of evidence for this is that duplication (or triplication) of the SNCA gene locus coding for alpha-synuclein, which increases alpha-synuclein levels by the seemingly modest amount of 50% (or 100%), causes patients to develop PD or LBD.
The ability to test hypotheses about how alpha-synuclein contributes to this neurodegeneration in living brain could benefit greatly from the development of new experimental strategies to visualize alpha-synuclein in vivo, including its function, metabolism and aggregation within neurons and glia. For these reasons, we have spent a significant amount of effort to develop new approaches to try and tackle these problems. Our work allows us (for the first time) to visualize alpha-synuclein in the living brain in mouse models of PD and LBD using in vivo multiphoton fluorescence microscopy through cranial windows. One goal of our work is to use these mouse models of PD and LBD, where alpha-synuclein is over-expressed, to understand in the living brain how increasing levels of this protein leads to its aggregation and subsequent neuronal dysfunction and cell death.
Our data demonstrate that we can visualize human alpha-synuclein fused to Green Fluorescent Protein (Syn-GFP) in the cortex of transgenic mice with cellular and synaptic resolution using this cranial window-based approach. Furthermore, we can follow individually labeled neurons and presynaptic terminals serially over a period of many months. We have paired this approach with alpha-synuclein preformed fibril seeding models to be able to image, for the first time, the formation of Lewy bodies in the living brain. Our work suggests that once a neuron forms a Lewy body it is destined to die within weeks to months, while nearby cells without Lewy bodies almost never die within this time frame. We are currently building on these strategies to test the hypothesis that alpha-synuclein may interact in vivo with other proteins relevant to neurodegeneration, like beta-amyloid and tau, and that these interactions are important for each protein’s ability to aggregate and contribute to disease.
Unexpected Roles for Synuclein in DNA Repair
Our in vivo imaging studies of alpha-synuclein aggregation in mouse models led us to postulate a new hypothesis for alpha-synuclein function in the cell nucleus in DNA double-strand break (DSB) repair. Although alpha-synuclein has been described as having a normal functional role in both the synapse and nucleus since its discovery (its name is a contraction of these two words), its function in the nucleus has been much less studied. Our observation that when a neuron forms a Lewy body it loses expression of soluble alpha-synuclein from the nucleus led us to consider whether a loss-of-function of alpha-synuclein could play a role in neurodegeneration. This work was inspired, in part, by work done by others in the pediatric cerebellar disorder Ataxia Telangiectasia, where deficiency of DSB repair is associated with Lewy body formation.
Our data demonstrate that alpha-synuclein colocalizes with multiple established DSB repair components within discrete nuclear foci in human cells and mouse brain. Alpha-synuclein knockout increases DSBs after treatment with the chemotherapeutic bleomycin and reduces DSB repair kinetics in human cells. Alpha-synuclein knockout mice show increased DSBs and this is rescued by transgenic reintroduction of human alpha-synuclein. Using a new, in vivo imaging approach that we developed, we find that synuclein is rapidly recruited to DNA damage sites in living mouse brain. Interestingly, Lewy body-bearing neurons in mouse model and patient tissue demonstrate increased DSBs. These data led us to propose a new function for alpha-synuclein in regulating DSB repair. We are currently advancing this work by studying the mechanism by which alpha-synuclein modulates DSB repair and directly testing its relevance for DSB repair in neurons.
Although the risk of all cancers is generally reduced in patients with neurodegenerative diseases, there are a few notable exceptions. The best described exception is the increased risk of melanoma in PD patients. Although the cause for this increased risk is currently unclear, melanoma does highly overexpress the same alpha-synuclein protein that aggregates in PD. Another goal of our lab is to test whether our recent discovery that alpha-synuclein is important for modulating DSB repair could provide useful insights into the mechanism behind this PD-melanoma association.
