Investigator:
Letizia Zanetti, PhD
Name of Institution:
The Trustees of Columbia University in the City of New York
Project Title:
Investigating Neuroinflammation in a Novel PrknR275W Mouse Model of PD
Investigator Bio:
Dr. Letizia Zanetti is a Post-Doctoral Research Scientist at Columbia University Irving Medical Center under the mentorship of Dr. David Sulzer and is focused on understanding the molecular mechanisms of Parkinson’s disease (PD). Her goal is to find therapeutic strategies to prevent the death of dopaminergic neurons. She pursued her doctoral studies at Vita-Salute San Raffaele University (2020-2023) in a program that combines an academic focus with a translational approach. During that time, she was awarded an eight-month Fresco Parkinson Institute Fellowship to work in Dr. Margaret Rice’s lab at New York University, studying dopamine release. For her postdoctoral training, she is continuing to build on her prior experience by studying the neuroimmunology of PD.
Objectives/Background:
Mutations in the PARK2 gene can cause autosomal recessive juvenile parkinsonism (ARJP), a rare form of PD that starts at a young age. During her PhD training, Dr. Zanetti developed the first genetically accurate ARJP mouse model that showed both brain changes and movement problems. She will be using this mouse model to pursue additional studies of the molecular underpinnings of PD. Evidence from human studies and animal models shows that inflammation plays a major role in Parkinson’s, even appearing 10-15 years before symptoms, with immune cells contributing to Parkinson’s-related cellular damage. Utilizing the ARJP mouse model, this project will explore how the immune system damages dopamine-producing brain cells and will help guide the development of new treatments, including the possible use of safe, already-approved drugs.
Methods/Design:
First, we will study the brain’s own immune response in the ARJP mouse model, looking at how cells like microglia and astrocytes change over time and interact with immune cells in the brain. We will use advanced imaging and cell analysis techniques to do this work. Next, we will study immune cells in the blood, focusing on T cells that enter the brain – how they send signals, and whether these responses differ between brain areas or between males and females. Together, this will give us a detailed map of how the immune system contributes to brain cell loss in PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This project will be critical for advancing the diagnosis and treatment of PD for two main reasons. First, this mouse model is the first to faithfully replicate a genetic form of the disease, allowing us to study its mechanisms in real time across different stages and to define the role of the immune system in disease development. Second, this approach can reveal key differences between patients and healthy individuals, potentially identifying warning signs for earlier and more accurate diagnosis. It can also pinpoint immune targets that could be used to develop new therapies or repurpose existing FDA-approved drugs.