Blood-Based Exosomal A-Synuclein Aggregates as a Quantifiable Biomarker of Parkinson s Disease
Abstract
Environmental neurotoxic chemical exposure has been increasingly recognized as a key etiological factor of sporadic Parkinson s disease (PD), and much evidence indicates that genetic and environmental factors can jointly influence the risk of developing this disease. Current research also suggests that aggregated a-synuclein (aSyn) protein, encoded by the major risk gene for PD SNCA, can be packaged into extracellular vesicles (EVs), including exosomes, thus propagating toxic aSyn aggregates through a non-cellular autonomous process. Despite these advances, deciphering the molecular mechanisms associated with the interaction between aSyn and chronic pesticide exposure and its role in the PD etiopathogenesis has been challenging. Furthermore, human cohort studies are challenged by the long latency between exposure and clinical diagnosis and lack of in vivo biomarkers capable of differentiating PD from clinically similar syndromes, capturing the distinctive pathological pattern and molecular characteristics, and/or tracking the progression of PD. Therefore, an objective and quantifiable biomarker is highly desired to monitor the gene-environment interactions in PD as well as to improve the clinical and differential diagnosis of PD. Recently, our lab successfully established a new biomarker assay called real-time quaking-induced conversion (RT-QuIC) for ultrasensitive detection and quantification of multiple disease-specific misfolded proteins, including aSyn and prions in clinical samples. Our RT-QuIC assay shows high sensitivity and specificity to detect misfolded aSyn in CSF and submandibular gland (SMG) samples from PD and dementia with Lewy body (DLB) subjects. Our collaborating team, Dr. Jing Zhang s lab at the University of Washington, recently reported erythrocytic red blood cell (RBC)-derived EVs are one of the major sources of aSyn in blood and can cross the BBB to evoke PD-relevant pathology in the brain. Our preliminary studies also reveal the potential utility of the aSyn RT-QuIC assay to detect aggregated aSyn protein from EVs isolated from neurotoxic pesticide-treated human RBCs. These exciting findings and existing literature lead to our premise that RT-QuIC detection of aSyn oligomers in RBC-derived EVs, including exosomes, constitutes a quantifiable biomarker of gene-environment interactions in PD. Leveraging two different cohorts of idiopathic PD patients led by Dr. Zhang and Dr. Ergun Uc at the Iowa City VA Health Care System (IC-VAHCS), respectively, this work will test the following three objectives. In Objective 1, we will characterize the effect of exposure to environmental neurotoxic pesticides on the abundance of RBC-derived EV aSyn aggregation in human RBC cultures and a human aSyn transgenic PD mouse model of pesticide neurotoxicity. In Objective 2, we will investigate the potential of misfolded aSyn in RBC-derived EVs as a biomarker in a large clinical PD cohort and a driver of PD pathogenesis in animal models of PD. In Objective 3, we will cross-validate misfolded aSyn in RBC-derived EVs as a biomarker for PD-related changes in a cohort of US veterans with neurotoxic chemical exposure history. Overall, we anticipate that our comprehensive approaches will yield highly reliable protein biomarkers for elucidating gene-environment interactions and early diagnosis of PD and its progression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010811
Entities
People
- Ergun Uc
Organizations
- Iowa City VA Medical Center
- United States Army