Investigator:
Julita Chlebowicz, PhD
Name of Institution:
Weill Medical College of Cornell University
Project Title:
Synaptic Vesicle Lipid Dyshomeostasis in Synucleinopathies
Investigator Bio:
Dr. Julita Chlebowicz is a postdoctoral associate in neuroscience at the Appel Institute for Alzheimer’s Disease and the Brain and Mind Research Institute at Weill Cornell Medicine in New York City, where she has been working since Fall 2023. She conducts research in the laboratory of Dr. Jacqueline Burré, focusing on synaptic vesicle lipid dyshomeostasis in synucleinopathies such as Parkinson’s disease (PD).
Dr. Chlebowicz earned her bachelor’s and master’s degrees in biotechnology from the Warsaw University of Technology in Poland. In 2016, she participated in a Fulbright Commission-supported traineeship at UT Southwestern Medical Center (UTSW) in Dallas, where she worked in the Department of Biophysics under the mentorship of Dr. Elizabeth Goldsmith. She began her Ph.D. in 2017 at UTSW and joined the laboratory of Dr. Marc Diamond to study the aggregation of alpha-synuclein, a hallmark of PD and other synucleinopathies as well as developing novel biosensors for detecting protein aggregation. In 2023 Dr. Chlebowicz earned her doctorate degree in cell and molecular biology, with a thesis entitled “Decoding sequence determinants of a-synuclein aggregation”.
Objectives/Background:
The goal of the project is to investigate lipid changes in mouse models of PD by studying the fat makeup of tiny sacs in the brain termed synaptic vesicles (SV) which store chemical messengers used in brain cell communication. One such brain messenger is dopamine, which plays a role in movement, reward, and motivation, and which is decreased in the brains of people with PD. PD pathology is also characterized by clumps of alpha-synuclein (aSyn). One of aSyn’s normal functions is to bind SVs and assist in brain cell communication, a process which doesn’t work well when aSyn clumps together. Because aSyn binds to specific SV lipids, changes in lipid type and composition can alter aSyn-SV binding and thus communication between brain cells. Preliminary data highlights specific lipid changes in PD mouse models. The project will investigate how these changes affect aSyn function – including aSyn-SV binding, brain cell communication, and aSyn clumping.
Methods/Design:
We will use cultured neurons derived from brains of mouse models of PD and alter their lipid composition by modifying the levels of enzymes that produce and break down these lipids. Using biochemical/cell biology lab and imaging tools, we will study how aSyn sticks to these sacs, how changes in fats affect brain communication, and how this leads to protein clumping in the brain.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Changes in lipid levels have been documented in brains of PD patients, but our understanding of the reasons, causes, and implications are unclear. On the other hand, alterations specifically in synaptic vesicle lipids have never been described or explored as factors involved in PD. These studies are expected to reveal new disease mechanisms and provide novel biomarkers and/or therapeutic targets for PD.