The function of α-synuclein

Abstract

Human genetics has indicated a causal role for the protein α-synuclein in the pathogenesis of familial Parkinson's disease (PD), and the aggregation of synuclein in essentially all patients with PD suggests a central role for this protein in the sporadic disorder. Indeed, the accumulation of misfolded α-synuclein now defines multiple forms of neural degeneration. Like many of the proteins that accumulate in other neurodegenerative disorders, however, the normal function of synuclein remains poorly understood. In this article, we review the role of synuclein at the nerve terminal and in membrane remodeling. We also consider the prion-like propagation of misfolded synuclein as a mechanism for the spread of degeneration through the neuraxis.

Figure 1

The N-terminus of synuclein contains 7 eleven residue repeats with the consensus sequence shown above and helical wheel to the right. The height of the single letter amino acid code indicates the probability of finding that particular residue in the repeats of human α-synuclein. Blue indicates basic, red acidic, purple polar uncharged and black nonpolar residues.

Figure 2

Over-expression of α-synuclein in rat hippocampal neurons inhibits synaptic vesicle exocytosis. Embryonic rat hippocampal neurons were transfected with VGLUT1-pHluorin and either wild type human α-synuclein or empty vector. After growth in culture for two weeks, the cells were stimulated at 10 Hz for 60 s and the response of VGLUT1-pHluorin monitored. Quenched at the low pH of synaptic vesicles, the pHluorin (a modified form of GFP shifted in its pH sensitivity) becomes more fluorescent when exposed to the external pH during exocytosis. The reacidification that follows endocytosis results in the quenching of fluorescence. NH₄Cl is used to alkalinize all of the intracellular VGLUT1-pHluorin pool, and demonstrates that synuclein over-expression does not reduce expression of the reporter. Over-expression of synuclein impairs the exocytosis of synaptic vesicles, but has no apparent effect on endocytosis after normalization to peak stimulated fluorescence. (Reproduced from Nemani et al., 2010)

Figure 3

Synuclein exhibits prion strain-like properties. Fibrils of recombinant synuclein were taken up by primary neurons and the derived fibrils used for repetitive seeding of additional primary cultures. Early passages yield fibrils capable of forming only inclusions of synuclein (strain A). Fibrils derived from subsequent passages produced robust tau pathology with less deposition of synuclein (strain B). Both strains may derive from the same initial fibrillization reaction (gray arrows), but it seems more likely that strain A converts into strain B. (Adapted from Guo et al., 2013)

Figure 4

α-Synuclein tubulates membranes in vitro. A, Recombinant α-synuclein (600 μM) clarifies an opaque solution containing phosphatidylglycerol with palmitoyl and oleoyl side chains (60 μM). (Varkey et al., 2010) (Republished with the permission of JBC). B, 20 μM recombinant α-synuclein was added to nonextruded, ~0.4 μm membranes containing a 1:1 mixture of dioleoyl phosphatidyl choline and dioleoyl phosphatidic acid (400 μM), and examined by negative staining electron microscopy (T.L., R.H.E., unpublished observations). Size bar indicates 100 nm.