Study Rationale: While aging is the greatest risk factor for development of Parkinson’s disease (PD), how aging promotes PD is not fully understood. Examining the role of cellular senescence, 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 mutant genes have reciprocal pathological interactions where; senescence causes PD relevant neuropathology; PD-linked mutant genes (a-synuclein, LRRK2, Vps35) causes premature senescence, and senescence participate in neuropathology caused by PD-linked genes.
Study Design: During the first four years, we showed that 1) increasing senescence in brain cells is sufficient to cause PD-relevant neurodegeneration, 2) PD-relevant pathology in neurons promote senescence, and 3) eliminating senescent cells decreases PD related pathology. In the next phase, we will define the molecular changes associated PD in models of senescence; define, via genetic approaches, cause-and-effect relationship between PD-associated neurodegeneration and senescence; and determine the common pathogenic pathways between senescence, models of PD, and human PD cases.
Impact on Diagnosis/Treatment of Parkinson’s disease: Our effort will yield novel mechanistic insights on how aging promotes PD, identify new biomarkers, and identify novel therapeutic targets for PD such as the use of senolytics (drugs that selectively eliminate senescent cells and are current in Phase II clinical trials) as novel disease modifying therapies for PD.
Next Steps for Development: Because senolytics are in phase II human trial for other indications, they can be applied to PD cases rapidly. Further, efforts can be made to screen for/develop additional senolytic compounds.