This platform is aimed at capitalizing on our recent research efforts in two parallel domains concerning alpha-synucleinopathies, including Parkinson disease (PD):

1. the discovery of cellular mediators driving neurodegeneration and
2. animal model development for capturing prodromal phase of movement disability.

Using state-of-art spatial transcriptomics on brain sections from a transgenic mouse model of prion-like aSyn pathology, we have studied gene expression changes at early and advanced stages of the disease. In our analyses, we have identified unique molecular signatures which reflect progression from non-symptomatic to symptomatic phase, with the added power of defining region-specific changes in neuronal and glial microenvironment. To establish relevance to human disease, several of the key transcripts have also been cross-validated in microarray datasets from 3 independent cohorts of PD patients, as well as in the CSF proteomics from one cohort. Some notable mediators include signaling mechanisms (GPR37, SPP1, ROCK2), along with control of glucose homeostasis in brain.

In parallel, we have refined an experimental paradigm based on early/prodromal brainstem aSyn pathology in PD within the gigantocellular nuclei (Braak stage I-II). This mouse model shows progressive decline in spontaneous activity (non-invasive 24-hour monitoring in home cage) and an early phenotype (within 2 months) of postural instability in the absence of gross motor weakness. Thus, combining the two, we have now established a preclinical framework with translational value in mechanism-based drug discovery and/or repurposing for PD and related diseases. In summary, this platform offers the possibility of assessing the therapeutic effects of candidate molecules on:

1. cellular phenotypes during disease progression
2. ibehavioral phenotype (bradykinesia and postural instability) within a short time frame.