Study Rationale:
Parkinson's disease involves multiple abnormal proteins—α-synuclein, tau, and TDP-43—that clump together in brain cells. These protein clumps don't act alone; they work together to damage the brain's ability to manage cellular stress and process genetic information properly. When cells experience chronic stress due to aging, inflammation, or exposure to environmental toxins, specialized cellular compartments called stress granules become rigid and trap essential proteins, thereby exacerbating the disease. Understanding how these proteins interact during stress could reveal new ways to prevent or treat Parkinson's disease.
Hypothesis:
Chronic cellular stress in the brain renders stress granules rigid, thereby trapping proteins essential for homeostasis and accelerating the progression of Parkinson's disease.
Study Design:
We will use innovative laboratory models, including 3D mini-brains created from patient cells, genetically-modified humanized preclinical models, and donated human brain tissues to understand how protein abnormalities develop and spread. Advanced techniques, such as human brain organoids, single-cell proteomics and high-density electrophysiology, will help pinpoint the cellular changes that occur during PD. The effects of potential treatments that restore normal cell function by dissolving harmful protein clusters will also be tested.
Impact on Diagnosis/Treatment of Parkinson’s disease:
The findings could help understand PD pathogenesis, identify specific disease subtypes, and develop targeted treatments that stop or reverse disease progression.
Next Steps for Development:
Promising discoveries will be tested further in preclinical studies, setting the stage for future clinical trials to evaluate these novel therapeutic strategies in PD patients.