Jason Vevea

Email: jvevea@wisc.edu


Postdoctoral Fellowship Neuroscience, University of Wisconsin, Madison, WI
Ph.D. Pathobiology & Molecular Medicine, Columbia University, New York, NY
M.Phil. Pathobiology & Molecular Medicine, Columbia University, New York, NY
M.A. Pathobiology & Molecular Medicine, Columbia University, New York, NY
B.Sc. Biochemistry & Molecular biology, University of Minnesota, Minneapolis, MN

Awards and Funding

Warren Alpert Foundation Distinguished Scholars Fellowship, 2020-2022

NIH Postdoctoral F32 Fellow, 2017-2020
Mentor: Dr. Edwin R Chapman
Program coordinator: Dr. Glen Nuckolls, grant # F32NS098604

F1000 Associate Faculty Member Travel Grant for Cell Biology Faculty, 2017

HHMI Med into Grad Program, 2010-2011
Clinical Mentor: Michio Hirano, M.D.

Professional Associations

Society for Neuroscience 2019-Present

F1000 Associate Faculty Member 2016-Present

Research Summary

Throughout my graduate career, my research interests focused on mechanisms governing mitochondrial inheritance and cellular fitness using Saccharomyces cerevisiae as a model organism. A highlight of my research career was the work performed describing mechanisms related to organelle dynamics and function in response to glycerophospholipid imbalance. Examining published synthetic genetic arrays, I was able to identify negative genetic interactions between genes involved with lipid biosynthesis and mitochondria and endoplasmic reticulum (ER) dynamics and homeostasis. This original observation led us to describe in detail the cellular response to impaired phosphatidylcholine biosynthesis. In yeast we described broad organelle trafficking defects, specifically related to mitochondria and the ER. These organelles normally cooperate during lipid biosynthesis and we found that while mitochondrial dynamics and localization were impacted, mitochondria largely maintained function. We examined the ER and found markers related to misfolded protein stress and an accumulation of lipid droplets (LDs) immediately adjacent to the ER. It turned out that the creation and destruction of these stress-induced LDs was critical for recovery of cellular health.

During these studies, we learned of a human congenital muscular dystrophy (CMD) caused by impaired phosphatidylcholine biosynthesis (CHKB CMD). This knowledge was a direct product from my Med into Grad training and clinical mentorship from Dr. Michio Hirano. This disease presents clinically as early onset muscle wasting, cardiomyopathy, a severe mental handicap, and mitochondrial enlargement and mislocalization in muscle biopsies. Our results from yeast led us to speculate that mitochondria may not be the only defect in this CMD. We investigated sarcoplasmic reticulum (SR) localization in patient samples and found the SR to be disorganized which led us to investigate calcium handling in the mouse model for this human CMD. We found evidence for altered calcium dynamics in dystrophic muscle fibers in the form of increased calcium sparks mediated through dysfunctional ryanodine receptor (RyR) calcium channels. These observations provide clinically testable hypotheses through modulation of RyR function via available small molecule RyR modulators.

For my postdoctoral work, I chose to switch from studying organelle and membrane trafficking in yeast to using primary neurons to examine membrane trafficking that supports the synaptic vesicle cycle. During this time, I developed a new method to acutely disrupt long-lived membrane proteins in post-mitotic cells. I named this method knockoff and demonstrated its superiority to current techniques (i.e. lox-Cre or Auxin degron). Application of knockoff to a synaptic vesicle (SV) membrane protein, synaptotagmin 1 (syt1), granted fast-acting druggable control of syt1 protein levels in a mature neuron. The dual function of syt1 as both an SV fusion promoter and a fusion clamp has been debated for decades. Using electrical and optical methods to monitor SV release, I showed that during acute syt1 degradation, synchronous release decreased (as expected), and spontaneous release increased concurrently. This provides strong evidence for the dual function of syt1 as a direct fusion clamp and a calcium sensitive trigger for synchronous release.

I would like to continue to use and modify knockoff in my career and apply it to disease relevant proteins and neuronal processes. Broadly, this ability to disassemble proteins in live cells as you are studying them will undoubtedly lead to a better understanding of your protein of interest. I’m fascinated with presynaptic function and the origin of neurodegeneration. In my career I’d like to study the mechanisms that neurons use to sustain the synaptic vesicle cycle over long periods of time including synaptic vesicle quality control and mitochondrial quality control.


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