Team Studer

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PD Functional Genomics | 2020

Defining the Cellular and Molecular Determinants of Variable Genetic Penetrance in Parkinson’s Disease

Study Rationale: Why do some people develop Parkinson’s disease (PD) while others do not? Although many genetic risk factors have been identified, researchers still cannot confidently answer this question, or explain how certain cells in the brain go from being healthy early in life to diseased in old age. Clearly, numerous complex factors are involved, and a systematic investigation of the key cellular and molecular players is necessary to understand and effectively treat this disease.

Hypothesis: Team Studer hypothesizes that single genetic factors are insufficient to cause PD — rather, that it is triggered by a combination of genetics, age-related factors, and their effects in different brain cells.

Study Design: Here, Team Studer proposes to dissect the genetic, age-related, and cell-type-specific factors that lead to PD using a collection of genetically diverse stem cells derived from patients. Using advanced methods pioneered by the team, they will convert these stem cells into the different types of brain cells implicated in PD — neurons, microglia, and astrocytes — allowing the team to investigate how genetic risk factors, the aging process, and these different cell types interact to trigger disease. Team Studer will assess how various combinations of these factors disrupt the function of brain cells using detailed molecular studies, microscopy, genetic manipulations, and biochemical measurements — building a computational network model of the factors that cause PD.

Impact on Diagnosis/Treatment of Parkinson’s Disease: This richer, fully human cell model of PD will provide an entirely new level of understanding of how the interplay between genetics, different brain cells, and aging shapes individual disease risk, enabling early diagnosis, prediction of therapeutic targets that could halt or reverse the disease, and stratification of patients into therapeutically meaningful subgroups.

Leadership
Lorenz Studer, MD
COORDINATING LEAD PI

Lorenz Studer, MD

Memorial Sloan Kettering Cancer Center
Gist Croft, PhD
CO-INVESTIGATOR

Gist Croft, PhD

New York Stem Cell Foundation
Joseph Powell, PhD
CO-INVESTIGATOR

Joseph Powell, PhD

Garvan Institute for Medical Research
Vikram Khurana, MD, PhD
CO-INVESTIGATOR

Vikram Khurana, MD, PhD

Brigham and Women's Hospital at the Harvard Medical School
Johannes Jungverdorben, PhD
Project Manager

Johannes Jungverdorben, PhD

Memorial Sloan Kettering Cancer Center

Project Outcomes

The project will not only help address the question of variable penetrance — why some individuals with genetic risk factors develop Parkinson’s disease while others do not — but may also lead to improved tools for early diagnosis, prediction of effective therapeutic targets, and stratification of patients into therapeutically meaningful subgroups. View Team Outcomes.

Team Outputs

Click the following icons to learn more about the team’s outputs

Overall Contributions

Here is an overview of how this team’s article findings have contributed to the PD field as of November 2023. There are two different categorizations of these contributions – one by impact to the PD community and a second by scientific theme.

Impact

Theme

Featured Output

Below is an example of a research output from the team that contributes to the ASAP mission of accelerating discoveries for PD.

Rapid iPSC inclusionopathy models shed light on the formation, consequence, and molecular subtype of α-synuclein inclusions

This work describes a new PD iPSC tool that models in a cell culture dish the advanced inclusion pathologies found in the human brain. Additionally, these inclusionopathy models provide clues to how distinct types of inclusions form, interact with each other, and differentially affect neuronal survival. Combining genome-scale proteomic and genomic screens, the authors identify key vesicle trafficking and actin cytoskeleton proteins that are sequestered within a specific inclusion subtype, enabling us to distinguish among distinct inclusion types in the patient postmortem brain.

Team Accolades

Members of the team have been recognized for their contributions.

Other Team Activities

  • Working Groups:
    • Senescence – Lorenz Studer and Isabelle de Luzy (Co-Chairs)
    • iPSC – Gist Croft (Co-Chair)

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