The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

The synucleins are a family of small, highly conserved proteins enriched in the vertebrate brain. Expression of α-synuclein (AS) is upregulated in association with song acquisition in zebra finch. Mutations in the protein cause a rare inherited form of Parkinson's disease, and AS aggregation is associated with sporadic Parkinson's and a number of other neurodegenerative disorders (Alzheimer's disease, dementia with Lewy bodies, multiple system atrophy, Down's syndrome).

My laboratory is applying a combination of molecular, biochemical, and cell culture approaches to determine the normal function of AS in neurons, and to elucidate the factors that influence pathological aggregation of AS. We have reported that AS is a lipid-binding protein with structural similarity to the exchangeable apolipoproteins, and that membrane binding leads to a major shift in protein conformation, from random coil to α-helix. We hypothesize that this change in conformation serves as a functional switch, and are currently pursuing several projects that focus on the interaction between synuclein and membranes as the key to its function:

1. Analysis of the structural determinants of phospholipase D2 inhibition by synucleins.
2. Phage display to identify peptides that influence the partitioning of α-synuclein between random coil (in solution), α-helix (in association with membranes), and β-sheet (in pathological aggregates).
3. Studies of folding and turnover of α-synuclein in cultured cells.
4. Analysis of the specificity of α-synuclein interactions with lipids, particularly long-chain polyunsaturated fatty acids, which catalyze irreversible oligomerization of the protein.