NIH Research Festival
Intracellular accumulation of Œ±-synuclein (Œ±-syn) amyloid fibrils is the pathological hallmark of synucleinopathies including Parkinson‚Äôs disease, Lewy body dementia, and multiple system atrophy. The gene that encodes for Œ±-syn (SNCA) engages in alternative splicing, generating at least three other isoforms (SNCA126, SNCA112, and SNCA98). For nearly 30 years, the vast amount of research dedicated to Œ±-syn has overlooked the potential involvement of these alternatively spliced variants. Of note, these alternatively spliced isoforms have been shown to be upregulated in synucleinopathies; however, neither their aggregation behaviors nor their effects on the full length Œ±-syn have been studied. To address this deficiency, we have carried out an in vitro investigation to examine their detailed aggregation behaviors as a function of protein concentration and solution pH and compared them to the full-length protein (SNCA140). Specifically, we are testing the hypothesis of whether specific isoforms can form different fibril polymorphs and facilitate fibril formation of SNCA140 by performing cross-seeding experiments. Aggregation kinetics were assessed by standard thioflavin-T assays, and fibril morphology and Œ≤-sheet formation are characterized by transmission electron microscopy and circular dichroism spectroscopy, respectively. It is anticipated that our results would offer new insights on the potential role of these variants in disease.
Scientific Focus Area: Biomedical Engineering and Biophysics
This page was last updated on Monday, September 25, 2023