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.

Representative Publications

Dynamic transport and localization of alpha-synuclein in primary hippocampal neurons.  Mong-Lin Yang, Linda Hasadsri, Wendy S Woods, Julia M George (2010) Molecular neurodegeneration 5 (1) p. 9     
http://www.ncbi.nlm.nih.gov/pubmed/20181133

Functional protein delivery into neurons using polymeric nanoparticles.  Linda Hasadsri, Jörg Kreuter, Hiroaki Hattori, Tadao Iwasaki, Julia M George (2009) The Journal of biological chemistry 284 (11) p. 6972-81  
http://www.ncbi.nlm.nih.gov/pubmed/19129199

Membrane-induced folding of the cAMP-regulated phosphoprotein endosulfine-alpha.  John M Boettcher, Kevin L Hartman, Daniel T Ladror, Zhi Qi, Wendy S Woods, Julia M George, Chad M Rienstra (2008) Biochemistry 47 (47) p. 12357-64  
http://www.ncbi.nlm.nih.gov/pubmed/18973346

Conformation-specific binding of alpha-synuclein to novel protein partners detected by phage display and NMR spectroscopy.  Wendy S Woods, John M Boettcher, Donghua H Zhou, Kathryn D Kloepper, Kevin L Hartman, Daniel T Ladror, Zhi Qi, Chad M Rienstra, Julia M George (2007) The Journal of biological chemistry 282 (47) p. 34555-67    
http://www.ncbi.nlm.nih.gov/pubmed/17893145

Structural determinants of PLD2 inhibition by alpha-synuclein.  Jacqueline E Payton, Richard J Perrin, Wendy S Woods, Julia M George (2004)  Journal of molecular biology 337 (4) p. 1001-9
http://www.ncbi.nlm.nih.gov/pubmed/15033366

Epitope mapping and specificity of the anti-alpha-synuclein monoclonal antibody Syn-1 in mouse brain and cultured cell lines.  R J Perrin, J E Payton, D H Barnett, C L Wraight, W S Woods, L Ye, J M George (2003)  Neuroscience letters 349 (2) p. 133-5
http://www.ncbi.nlm.nih.gov/pubmed/12946570

The synucleins.  Julia M George (2002)  Genome biology 3 (1) p. REVIEWS3002
http://www.ncbi.nlm.nih.gov/pubmed/11806835

Exposure to long chain polyunsaturated fatty acids triggers rapid multimerization of synucleins.  R J Perrin, W S Woods, D F Clayton, J M George (2001)  The Journal of biological chemistry 276 (45) p. 41958-62
http://www.ncbi.nlm.nih.gov/pubmed/11553616

Interaction of Human alpha -Synuclein and Parkinson's Disease Variants with Phospholipids. STRUCTURAL ANALYSIS USING SITE-DIRECTED MUTAGENESIS
R J Perrin, W S Woods, D F Clayton, J M George (2000)  Journal of Biological Chemistry 275 (44) p. 34393-34398
http://www.ncbi.nlm.nih.gov/pubmed/10952980

Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. W S Davidson, A Jonas, D F Clayton, J M George (1998)  The Journal of biological chemistry 273 (16) p. 9443-9
http://www.ncbi.nlm.nih.gov/pubmed/9545270

Characterization of a novel protein regulated during the critical period for song learning in the zebra finch.  J M George, H Jin, W S Woods, D F Clayton (1995)  Neuron 15 (2) p. 361-72

Complete Publications List