Identification of Alpha-synuclein Molecular Forms Correlating with Clinicopathology of Parkinson's Disease
Clinicopathological Correlations of Parkinsonís Disease, 2009
The research from this grant has continued with the supplementary grant:
- Identification of alpha-synuclein molecular forms correlating with clinicopathology of Parkinson's disease
A systematic characterization of alpha-synuclein from human tissue using high-resolution mass spectrometry has not been reported. A detailed study of alpha synuclein modifications and cleavage products in normal and Parkinson’s brain samples will be undertaken by our group in collaboration with the Arizona Parkinson's Disease Consortium. Identifying unique forms of alpha-synuclein and their correlation to clinical symptoms and progression of Parkinson’s disease will lead to a better understanding of the role of this protein in Parkinson’s disease.
Alpha-synuclein will be isolated from samples of postmortem Parkinson’s and normal brain regions by using antibodies to alpha-synuclein. The purified alpha-synuclein will be analyzed by high-resolution mass spectrometry using top down and bottoms up proteomics approaches to determine processing and modifications of alpha-synuclein in normal and Parkinson’s brains at various stages of the disease.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Understanding the forms of alpha-synuclein and their relationship to stages of Parkinson’s disease could lead to a molecular biomarker of disease progression and possible insights into new avenues for treatment of this disease.
The results will yield critical insights into the form of alpha-synuclein that is associated with Parkinson’s disease symptoms and progression. These insights could inform disease-associated biomarkers as well as potential molecular targets for therapeutic interventions to slow disease progression.
INTERIM PROGRESS REPORT
We have developed a sensitive method for profiling alpha synuclein and its processed forms (“alpha synucleome”) from human brain tissue using mass spectrometry. We now report on a pilot study where we analyzed the alpha synucleome from the 6-25 mg of frontal cortex of normal, Parkinson’s disease, and dementia with lewy bodies (DLB) tissues received from the APDC. Our data show that the majority of alpha synuclein present is acetylated, full length alpha synuclein. Interestingly, the amount of truncated and phosphorylated alpha synuclein was minimal in the total extracts of the cortex and did not differ between normal controls and disease tissues. On the other hand, oxidated alpha synuclein levels were significantly higher in normal controls than in the two disease groups. Our observations requires additional studies on differentially extracted brain tissues to determine the presence of modified alpha synuclein in distinct human alpha synucleopathies.
President and CSO at TransThera Consulting Co.
Adjunct Professor of Neurology at Northwestern University Feinberg School of Medicine
Location: Portland, Oregon