Promising Outcomes of Original Grant:
We have developed a sensitive method for profiling alpha synuclein and its processed forms (“alpha synucleome”) from minimal clinical model brain tissue using high resolution top down mass spectrometry methods. In total extracts of autopsied frontal cortex from Parkinson’s disease, Dementia with Lewy Bodies (DLB) and normal control subjects, the majority of alpha synuclein is present as the acetylated, full length protein. Unexpectedly, the amount of truncated or modified alpha synuclein was minimal and did not significantly differ between normal control and disease tissues. These observations require further studies to determine the type and quantity of pathology-associated alpha synuclein.
Objectives for Supplemental Investigation:
The current application proposes to continue our collaboration with Arizona Parkinson’s Disease Consortium (APDC) to leverage patient-derived tissues and associated clinical and pathological data to advance our understanding of the role of alpha-synuclein in disease pathology. We will make quantitative assessment of various forms of alpha synuclein in the frontal cortical extracts enriched for Lewy bodies and compare the same to total extracts in order to rigorously test the current prevalent hypotheses implicating phosphorylation and truncation of alpha synuclein in the pathogenesis/pathphysiology of PD. These studies will provide, for the first time, quantitative understanding of true levels of various alpha-synuclein modifications associated with Lewy bodies and its correlation to clinical symptoms. It is possible also that we will identify other hitherto unknown alpha synuclein modifications.
Importance of This Research for the Development of a New PD Therapy:
The studies proposed in the current application will identify the nature and amount of pathology-associated alpha synuclein in Parkinson’s disease. This information could yield insights into potential molecular approaches for therapeutic interventions to slow disease progression. Additionally, we may identify a biomarker(s) of disease pathology that could be used to facilitate drug development.