Abstract
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.
Highlights
␣-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)
We found that in cells loaded with high concentrations of fatty acids, wild type synuclein redistributed from the cytosol to the surface of triglyceride-rich lipid droplets
Wild type and PD mutant synucleins displayed primarily cytosolic distributions, plasma membrane staining was often observed for wild type and A53T synucleins (Fig. 1, a– c)
Summary
Vol 277, No 8, Issue of February 22, pp. 6344 –6352, 2002 Printed in U.S.A. Lipid Droplet Binding and Oligomerization Properties of the Parkinson’s Disease Protein ␣-Synuclein*. In cells treated with high concentrations of fatty acids, wild type ␣-synuclein accumulated on phospholipid monolayers surrounding triglyceride-rich lipid droplets and was able to protect stored triglycerides from hydrolysis. Chemical cross-linking demonstrated that synuclein formed small oligomers within cells, primarily dimers and trimers, that preferentially associated with lipid droplets and cell membranes. To investigate the membrane binding capacity of ␣-synuclein within cells, we examined the distribution of wild type and PD mutant synucleins in both immortalized cell lines and primary neuronal cultures. We found that in cells loaded with high concentrations of fatty acids, wild type synuclein redistributed from the cytosol to the surface of triglyceride-rich lipid droplets. We found that the binding of wild type synuclein to lipid droplet surfaces altered subsequent triglyceride metabolism, whereas the expression of PD mutant synucleins had little effect. Our results suggest that the structural alterations that occur upon binding of ␣-synuclein to membranes may prime its oligomerization to form potentially toxic intermediates or progress into synuclein fibrils observed in brains of patients with various synucleinopathies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
