Interestingly, some individuals with the G2019S mutation, known as the non-manifesting carrier (NMC) group, have not developed PD yet. Out of many mutations in LRRK2, Gly2019→Ser (G2019S) mutation in its kinase domain is by far the most common among caucasians 16. LRRK2 encodes a large protein of 2527 amino acids containing two functional enzymatic domains, the GTPase and the Ser/Thr kinase domains, and several protein–protein interaction domains such as the armadillo, ankyrin, leucine-rich repeat (LRR), and WD40 domains 14, 15. Mutations in LRRK2 have been recognized as genetic risk factors for sporadic (~1%) and familial forms of PD (~5%) 13.
Specifically, mutations in the Leucine-rich repeat kinase 2 ( LRRK2) gene are found in hereditary forms, emphasizing the shared molecular pathway driving both familial and non-familial PD to comprise the most common cause of the disease 12, 13. A subset of patients develops PD because of a major genetic risk. Large-scale genome-wide association studies (GWAS) have identified 41 independent risk variants for PD in various cohorts 4, 11. While the cause of PD is currently unknown, researchers speculate that environmental and genetic factors contribute to its development 10. Overall, as many as 1 million Americans are living with PD, and approximately 60,000 Americans are diagnosed with PD each year 8, 9. It has been estimated that PD affects 1 percent of the population over 60 7. Currently, PD is incurable and progresses gradually with symptom deterioration into severe disabilities 6. In addition to motor symptoms, non-motor symptoms may include cognitive impairment, autonomic dysfunction, hyposmia, and sleep disturbances 5. PD’s most common pathological finding is a decreased pigmentation in the substantia nigra pars compacta (SNpc) caused by the death of dopaminergic neurons, leading to progressive deterioration of motor function 3, 4. PD is the second most common neurogenerative disorder after Alzheimer’s disease (AD) 2.
It has been more than two centuries since Parkinson’s disease (PD) was described by Dr. These findings demonstrate a general strategy of utilizing biofluid EV proteome/phosphoproteome as an outstanding and non-invasive source for a wide range of disease exploration.
Several putative disease biomarkers are further partially validated in patients with PD using parallel reaction monitoring (PRM) and immunoassay for targeted quantitation. We establish a panel of proteins and phosphoproteins as novel candidates for disease biomarkers and substantiate the biomarkers using machine learning, ROC, clinical correlation, and in-depth network analysis. We detect multiple proteins and phosphoproteins elevated in PD EVs that are known to be involved in important PD pathways, in particular the autophagy pathway, as well as neuronal cell death, neuroinflammation, and formation of amyloid fibrils. ResultsĪfter efficient isolation of urinary EVs through chemical affinity followed by mass spectrometric analyses of EV peptides and enriched phosphopeptides, we identify and quantify 4476 unique proteins and 2680 unique phosphoproteins. Utilizing 138 urine samples from four groups, healthy individuals (control), healthy individuals with G2019S mutation in the LRRK2 gene (non-manifesting carrier/NMC), PD individuals without G2019S mutation (idiopathic PD/iPD), and PD individuals with G2019S mutation (LRRK2 PD), we applied a proteomics strategy to determine potential diagnostic biomarkers for PD from urinary extracellular vesicles (EVs). However, compared to cancer, fewer genetic mutations contribute to the cause of PD, propelling the search for protein biomarkers for early detection of the disease. Mutations in the leucine-rich repeat kinase 2 ( LRRK2) gene have been recognized as genetic risk factors for Parkinson’s disease (PD).
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