Lipid droplet binding and oligomerization properties of the Parkinson's disease protein alpha-synuclein.
alpha-Synuclein is a major component of the fibrillary lesion known as Lewy bodies and Lewy neurites that are the pathologic hallmarks of Parkinson's disease (PD). In addition, point mutations in the alpha-synuclein gene imply alpha-synuclein dysfunction in the pathology of inherited forms of PD. alpha-Synuclein is a member of a family of proteins found primarily in the brain and is concentrated within presynaptic terminals. Here, we address the localization and membrane binding characteristics of wild type and PD mutants of alpha-synuclein in cultured cells. In cells treated with high concentrations of fatty acids, wild type alpha-synuclein accumulated on phospholipid monolayers surrounding triglyceride-rich lipid droplets and was able to protect stored triglycerides from hydrolysis. PD mutant synucleins showed variable distributions on lipid droplets and were less effective in regulating triglyceride turnover. Chemical cross-linking demonstrated that synuclein formed small oligomers within cells, primarily dimers and trimers, that preferentially associated with lipid droplets and cell membranes. Our results suggest that the initial phases of synuclein aggregation may occur on the surfaces of membranes and that pathological conditions that induce cross-linking of synuclein may enhance the propensity for subsequent synuclein aggregation.
Cole
Nelson B
NB
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health Bethesda, Maryland 20982, USA. ncole@nhgri.nih.gov
Murphy
Diane D
DD
Grider
Theresa
T
Rueter
Susan
S
Brasaemle
Dawn
D
Nussbaum
Robert L
RL
D019943:Amino Acid Substitution; D002460:Cell Line; D003001:Cloning, Molecular; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D016631:Lewy Bodies / Q000473:pathology; D008049:Lipase / Q000378:metabolism; D050356:Lipid Metabolism; D046911:Macromolecular Substances; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D051843:Synucleins; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism*; D051844:alpha-Synuclein
D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051843:Synucleins; D014280:Triglycerides; D051844:alpha-Synuclein; D008049:Lipase