Study Rationale: Lysosomal impairment is strongly implicated in the pathology of Parkinson’s disease (PD). Loss-of-function mutations in ATP13A2, a gene that encodes a lysosomal protein, are causally linked to a form of early-onset atypical Parkinson’s disease. A second lysosomal protein, an enzyme called cathepsin K, has great affinity for alpha-synuclein, which forms aggregates in the brains of people with PD.
Hypothesis: We hypothesize that ATP13A2 and cathepsin K hold promise as biomarkers for PD.
Study Design: In this study, we will investigate whether measuring ATP13A2 and cathepsin K will allow monitoring of neurodegeneration and alpha-synuclein aggregation in biological fluids from preclinical models of a variety of neurodegenerative diseases, including PD, multiple system atrophy and progressive supranuclear palsy. Additionally, we will establish the sensitivity and specificity of both targets as putative biomarkers by leveraging current body fluid biobanking collections that include individuals with different neurodegenerative diseases associated clinically with parkinsonism.
Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, this project will represent a significant breakthrough in our ability to design a specific lysosomal biomarker for PD. Such biomarkers will lead to an improved understanding of the contribution made by lysosomes to the pathology and progression of PD.
Next Steps for Development: Our findings will aid in the design and validation of disease-modifying lysosomal therapies for treating PD and related synucleinopathies. The method we develop could also transform our ability to study other neurodegenerative diseases associated with the deposition of protein aggregates, such as tauopathies.