Team Lee

Expand to Read More +Collapse to Read Less –
PD Functional Genomics | 2020

Senescence in Parkinson’s Disease and Related Disorders

Study Rationale: While aging is the greatest risk factor for the development of Parkinson’s disease (PD), how aging promotes PD is not fully understood. Examining the role of cellular senescence (deterioration of function), a major driver of aging, in PD represents a completely novel approach to understanding disease pathophysiology and may lead to new therapeutic approaches.

Hypothesis: Senescence and PD-linked gene mutations have reciprocal pathological interactions where (i) senescence causes PD-relevant neuropathology; (ii) PD-linked mutant genes (alpha-synuclein, LRRK2, Vps35) cause premature senescence; and (iii) senescence participates in neuropathology caused by PD-linked genes.

Study Design: First, Team Lee will use novel mouse models of premature senescence to test whether premature senescence in specific cell types causes PD-like neuropathology. Second, they will combine mouse models of senescence and familial PD to test whether senescence participates in neuropathology caused by mutant PD-linked genes. Specifically, Team Lee will determine if pathology in a PD mouse model causes premature senescence and whether removing senescent cells from brain can prevent PD pathology. Finally, Team Lee will perform gene expression analysis of PD brains and mouse brains, at a single-cell level, to gain high-resolution insights about cellular processes that link aging and PD pathology.

Impact on Diagnosis/Treatment of Parkinson’s Disease: Team Lee’s results will support the use of senolytics (drugs that selectively kill senescent cells and are currently in Phase II clinical trials) as novel disease-modifying therapies for PD. In addition, Team Lee’s studies may identify new biomarkers of senescence in PD.

Leadership
Michael Lee, PhD
COORDINATING LEAD PI

Michael Lee, PhD

University of Minnesota
Darren Moore, PhD
CO-INVESTIGATOR

Darren Moore, PhD

Van Andel Institute
Laura Niedernhofer, MD, PhD
CO-INVESTIGATOR

Laura Niedernhofer, MD, PhD

University of Minnesota
Jane Balster, MA
Project Manager

Jane Balster, MA

University of Minnesota
Michael Henderson, PhD
Co-Investigator

Michael Henderson, PhD

Van Andel Institute

Project Outcomes

This project will determine if cellular senescence is a pathogenic component of Parkinson’s disease and test if drugs targeting senescent cells can be used as a disease-modifying therapy for PD. 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.

Adult-onset deletion of ATP13A2 in mice induces progressive nigrostriatal pathway dopaminergic degeneration and lysosomal abnormalities

ATP13a2 loss-of-function mutations are associated with early onset Parkinson’s disease, characterized by severe neurodegeneration. However, germline ATP13a2 KO mouse models do not exhibit this neurodegeneration, even with advanced age. By depleting ATP13a2 from the brain of mature, adult mice, Team Lee was able to recapitulate ATP13a2 pathology and neurodegeneration that is seen in humans.

Team Accolades

Other Team Activities

  • Working Group: Senescence – Michael Lee (Co-Chair)

In the News

Be a part of a global initiative to influence the culture of the way we do science.