Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by motor symptoms including resting tremor, bradykinesia and rigidity. The clinical manifestations of this disorder are caused by degeneration of dopaminergic neurons in the substantia nigra that are related to abnormal accumulation of the protein, α-synuclein in oligomers, fibrils and eventually in Lewy bodies. The actual clinical diagnosis of PD is currently made through patient neurologic examination and history and is based predominantly on evaluation of motor symptoms. Motor changes, however, present when there is already loss of 30-70% of dopaminergic neurons in the substantia nigra. Thus, there is an unmet need for a biomarker that can reliably aid in disease diagnosis prior to the onset of symptoms and inevitable progression of this disabling disease.
Here we test the hypothesis that characteristic changes in extracellular vesicle (EV) composition and contents may serve as biomarkers for PD. EVs are membrane-encapsulated vesicles containing signaling molecules (lipids, proteins, RNAs) and other components that are actively secreted and recaptured by cells, mediating local and distal cell-cell signaling. EVs may also contain protein aggregates such as the abnormal accumulations of α-synuclein in PD. A particularly novel feature of our search for a diagnostic EV biomarker in PD is our use of tear fluid as our principal source for biomarker discovery, supported by findings in the literature that neuronally-derived EVs are recovered in tears. We propose to enroll PD patients and healthy control subjects to contribute tear fluid and cerebrospinal fluid (CSF) to enable two Specific Aims:
Aim 1: To identify characteristic properties of tear EVs including composition, contents, and abundance in patients with PD and HC subjects.
Aim 2: To compare tear EVs and cerebrospinal fluid EVs from the same subject to determine if they have comparable properties.