Characterization of PP2A as a Novel Therapeutic Target and a Biomarker of PD

Objective/Rationale: 
Protein phosphatase 2A (PP2A) is a key enzyme that dephosphorylates proteins. PP2A deficits may be critical causes of Parkinson’s disease (PD) - abnormalities in PP2A levels and activity have been linked to other neurodegenerative disorders and aberrant phosphorylation of alpha-synuclein is a key feature of PD.  We aim to conclusively verify connection between PP2A activity and development of PD using postmortem brain samples to guide therapeutic development and as a biomarker of disease progression.

Project Description: 
Postmortem tissue samples collected from Parkinson’s disease (PD) patients are an invaluable resource to understand the causes of disease and validate potential therapeutic targets. Levels, chemical modification status, and activity of protein phosphatase 2A (PP2A) in samples from a number of PD patients, compared to Alzheimer’s disease and normal subjects, will be assessed using a range of methodologies. Changes will be assessed in the cortical regions of the brain as well as the substantia nigra, a key region which degenerates in the disorder. State of the art technologies including biochemical assessment, immunohisotchemistry and mass spectrometry will be applied. These studies will be performed in collaboration with key scientific leaders in academia. Upon successful completion, a new therapeutic target and a potential biomarker of PD will emerge.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:  
Successful verification of PP2A as a key player in pathogenesis of Parkinson’s disease will provide a new target for therapeutic development. Furthermore, as PP2A is a highly abundant enzyme in brain and other tissues, there is potential that disease related changes in PP2A could be developed as biomarkers for diagnostic purposes.  

Anticipated Outcome: 
These studies are expected to demonstrate whether there are changes in PP2A that are linked to Parkinson’s disease and related neurodegenerative disorders.  We can use this information to drive therapeutic development and develop biomarker strategies to ultimately develop efficacious drugs for Parkinson’s disease.