Abstract
α-Synuclein is a neuronal protein that is at the center of focus in understanding the etiology of a group of neurodegenerative diseases called α-synucleinopathies, which includes Parkinson’s disease (PD). Despite much research, the exact physiological function of α-synuclein is still unclear. α-Synuclein has similar biophysical properties as apolipoproteins and other lipid-binding proteins and has a high affinity for cholesterol. These properties suggest a possible role for α-synuclein as a lipid acceptor mediating cholesterol efflux (the process of removing cholesterol out of cells). To test this concept, we “loaded” SK-N-SH neuronal cells with fluorescently-labelled cholesterol, applied exogenous α-synuclein, and measured the amount of cholesterol removed from the cells using a classic cholesterol efflux assay. We found that α-synuclein potently stimulated cholesterol efflux. We found that the process was dose and time dependent, and was saturable at 1.0 µg/mL of α-synuclein. It was also dependent on the transporter protein ABCA1 located on the plasma membrane. We reveal for the first time a novel role of α-synuclein that underscores its importance in neuronal cholesterol regulation, and identify novel therapeutic targets for controlling cellular cholesterol levels.
Highlights
IntroductionSynuclein is a 140-amino acid protein produced predominantly by neurons in the brain
Introduction αSynuclein is a 140-amino acid protein produced predominantly by neurons in the brain.It is at the center of focus in understanding the etiology of a group of neurodegenerative diseases called α-synucleinopathies
The common feature of α-synucleinopathies is the presence of proteinaceous bodies containing aggregates of α-synuclein. α-Synuclein is normally present at the presynaptic terminals of neurons, where it is thought to play a role in maintaining a supply of synaptic vesicles. α-Synuclein is encoded by the SNCA gene and polymorphism and mutation studies of SNCA have provided evidence for a causal link between α-synuclein and Parkinson’s disease (PD) [4,5,6,7]
Summary
Synuclein is a 140-amino acid protein produced predominantly by neurons in the brain. It is at the center of focus in understanding the etiology of a group of neurodegenerative diseases called α-synucleinopathies. These include Parkinson’s disease (PD), dementia with Lewy bodies (DLB) [1], multiple system atrophy (MSA) [2], and a number of less well-characterized neuroaxonal dystrophies [3]. The causal link exists for DLB, but not for MSA [13]
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