LRRK2 and Other Novel Exosome Proteins in Parkinson's Disease (U18)
The cause of Parkinson's disease in most people is not known. Sometimes Parkinson's disease can be passed on from one family generation to the next, and scientists have recently identified the reasons for Parkinson's disease in some of these families. It turns out that there are rare differences in particular proteins in families that inherit Parkinson's disease from one generation to the next. One of these proteins is called LRRK2 (pronounced "Lark too"). LRRK2 may help scientists find out what is going on in Parkinson's disease by providing critical information about the disease process in regards to small changes in the LRRK2 protein. This critical information may be used to develop therapies that cure the disease, but may also be instrumental in identifying the people who are at risk for getting Parkinson's disease in the future. Dr. West and his team have recently found that LRRK2, and other proteins thought to be important in Parkinson's disease, are detectable in some components of normal urine, a biofluid that everybody gets rid of on a daily basis. Using newly developed technology that allows the West laboratory to measure these proteins, they will determine whether these proteins in urine are different in people with Parkinson's disease versus people without Parkinson's disease. They will also see if these proteins are lower in other people (people with Cancer, not Parkinson's) who are being treated with a particular medication (a Cancer treatment) which is thought to impact the activity of LRRK2. This will be helpful in determining if those urinary components could be used to help find cures for Parkinson's disease in treatment trials that are designed to destroy the activity of LRRK2. Finally, if LRRK2 is not the answer, the team is also measuring nearly one-thousand other proteins in PD patients and healthy control subjects to see if there are other differences between people with and without PD.
It is generally recognized that there are inadequate measures of detecting disease progression and biochemical pathways associated with Parkinson's disease (PD) in clinical populations, and that this lack of effective biomarkers has hindered, and is expected to continue to impede, successful clinical trials for efficacious neuroprotective (disease-retarding or halting) therapeutics. Genetic and pathological studies have identified several proteins linked to late-onset PD, and these proteins have provided insight into pathways that might be central to disease. However, these proteins have been difficult to analyze in PD cases due to the limited availability of disease-susceptible tissue, and studies are usually confined to post-mortem derived specimens. We have made the recent observation that LRRK2, and other proteins linked genetically and pathologically to PD, are detectable in exosomes isolated from human urine samples. Using a multiplex mass spectrometry approach, we can quantify 935 proteins from clinical urine exosome samples, and 140 of these proteins are linked to neurodegeneration by pathway analysis. This proposal seeks to 1) determine whether there are biomarkers associated with PD susceptibility and/or progression in urinary exosome-proteomes derived from PD patients versus controls, and 2) to determine if LRRK2 expression and/or phosphorylation are significantly lowered in the urinary exosomes of individuals treated with the potent LRRK2 kinase inhibitor sunitinib (a multi-kinase inhibitor compound), to establish an assay for on-target effects for future LRRK2 inhibitor clinical trials. Potential biomarkers of interest will be validated in replication cohorts, and the most promising leads will be further explored in future multi-center studies.
Goals of Project
- Resource building: Establish initial urinary exosome samples and pools from PD cases and controls, and estimate heterogeneity and power in proteomic analysis, through application of technology for whole proteomic screening and PD-targeted protein measurements in control urinary exosome samples. These technologies need to be applied to PD populations so sources of power and error can be identified and addressed.
- Discovery: Determine whether there are changes in urinary exosome proteins significantly associated with PD progression and susceptibility. We will also determine if LRRK2 expression or LRRK2 phosphorylation levels are lowered in patients receiving treatment with sunitinib (a potent kinase inhibitor).
- Replication: Targets of interest identified above will need to be validated in a new case/control series to separate idiosyncratic changes and false-positives from robust biomarkers (for PD and LRRK2 activity).
- 200 Parkinson's disease participants (varying stages of disease)
- 200 Healthy participants (various ages)
Congratulations, to the University of Alabama (Birmingham) for enrolling 581 participants into their PDBP project as of June 3, 2016 and completing, through the PDBP Data Management Resource, electronic documentation for 566 baseline visits!
LRRK2 secretion in exosomes is regulated by 14-3-3, Frasier et al., Human Molecular Genetics V22, 4988-5000