A male zebra finch learns a song by listening to a tutor, but song learning is normally restricted to a critical period in juvenile development. Here we identify an RNA whose expression in the song control circuit is altered during this critical period. The RNA encodes a soluble presynaptic protein that forms a predicted amphipathic alpha helix typical of the lipid-binding domain in apolipoproteins. We show this protein, which we call synelfin, to be the homolog of the human non-A beta component (and its precursor) recently purified from Alzheimer's disease amyloid. We suggest this highly conserved protein may serve a novel function critical to the regulation of vertebrate neural plasticity.

␣-Synuclein has been centrally implicated in neurodegenerative disease, and a normal function in developmental synaptic plasticity has been suggested by studies in songbirds. A variety of observations suggest the protein partitions between membrane and cytosol, a behavior apparently conferred by a conserved structural similarity to the exchangeable apolipoproteins. Here we show that the capacity to bind lipids is broadly distributed across exons 3, 4, and 5 (encoding residues 1-102). Binding to phosphatidylserine-containing vesicles requires the presence of all three exons, while binding to phosphatidic acid can be mediated by any one of the three. Consistent with a "class A2" helical binding mechanism, lipid association is disrupted by introduction of charged residues along the hydrophobic face of the predicted ␣-helix and also by biotinylation of conserved lysines (which line the interfacial region). Circular dichroism spectroscopy reveals a general correlation between the amount of lipid-induced ␣-helix content and the degree of binding to PS-containing vesicles. Two point mutations associated with Parkinson's disease have little (A30P) or no (A53T) effect on lipid binding or ␣-helicity. These results are consistent with the hypothesis that ␣-synuclein's normal functions depend on an ability to undergo a large conformational change in the presence of specific phospholipids.

No abstract

α-Synuclein (AS) fibrils are the major component of Lewy bodies, the pathological hallmark of Parkinson’s disease (PD). Here, we use results from an extensive investigation employing solid-state NMR to present a detailed structural characterization and conformational dynamics quantification of full-length AS fibrils. Our results show that the core extends with a repeated structural motif. This result disagrees with the previously proposed fold of AS fibrils obtained with limited solid-state NMR data. Additionally, our results demonstrate that the three single point mutations associated with early-onset PD—A30P, E46K and A53T—are located in structured regions. We find that E46K and A53T mutations, located in rigid β-strands of the wild-type fibrils, are associated with major and minor structural perturbations, respectively.

This is the first study to show the direct effects of α-synuclein on synaptic vesicle trafficking and to elucidate the underlying structural mechanisms. Acutely increasing α-synuclein severely inhibits synaptic vesicle recycling from the plasma membrane. The endocytic defects require a properly folded N-terminal α-helical domain of α-synuclein.