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.
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.
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.
Below is an example of a research output from the team that contributes to the ASAP mission of accelerating discoveries for PD.
Prior studies regarding the impact of tau on alpha-synuclein pathology and neuronal dysfunction have produced conflicting results. Team Lee sought to address the discrepancies by analyzing the impact of the loss of tau protein on disease progression. In this work, the authors’ findings indicate that a loss of tau protein reduces disease progression and neurodegeneration in a synucleinopathy-based mouse model, suggesting that tau may be involved in facilitating mechanisms that lead to neurodegenerative processes.