Using Digital Spatial Profile to Screen Targetable Molecules to Halt Alpha-Synucleinopathy

Project Summary

This project will leverage digital spatial profiling technology to examine multiple molecular targets on immune-oncology pathways at different pathological progression stages of PD (Braak stages) using patient post-mortem tissue. If successful, this effort has the potential of identifying novel molecular targets for early diagnosis and treatments, as well as establishing a timeline of immunopathological correlation with PD.

Principal Investigator

Professor Glenda Halliday

Study Rationale

Accumulating evidence indicates that immune dysfunction is involved in the onset and progression of the a-synuclein brain pathology underlying Parkinson’s disease, but of the many known immune molecules, those that could cause the dysfunction in the brain remain unknown. The immune resident cells in the brain are microglia and these work in concert with the support cells called astrocytes to protect neurons. These immune and supporting cells clear anything detrimental to the brain, including a-synuclein pathology, by using a variety of different immune molecules. We will use a new technique to reveal key immune molecules in donated brain tissue from Parkinson patients to identify any dysfunction and targetable molecules associated with increased a-synuclein brain pathology.

Hypothesis:

Changes in well-known immune molecules will occur in regions of neurodegeneration in the brains of patients with Parkinson’s disease, and will associate with increasing a-synuclein brain pathology.

Study Design:

Brain sections from Parkinson patients at different stages (before symptoms in people with a-synuclein brain pathology, early following diagnosis, and late in disease) will be used. 27 well-known immune molecules will be screened in these sections using a new technique that quantifies proteins to an individual molecule level. The molecules that change the most will be validated using traditional methods. Analysis will reveal immune function changes in cells in the brain over the disease course.

Impact on Diagnosis/Treatment of Parkinson’s disease:

This project will screen well-known immune molecules that are already targeted for treatment in immune system diseases and identify any substantive changes over time at a cellular level. Identifying substantive changes in these molecules in brain cells would provide novel targets for therapeutic development and for the development of peripheral assays for biomarker diagnosis.

Next Steps for Development:

Assess any molecular changes in peripheral tissue samples in PD patients at similar disease stages to examine their value in monitoring disease progression and early diagnosis. Determine whether there are any clinically approved interventions for the molecules identified and examine their effects in mouse models.