Chandra S, Chen X, Rizo J, Jahn R, Südhof TC.
A broken alpha -helix in folded alpha -Synuclein.
J Biol Chem. 2003 Apr 25;278(17):15313-8.
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This is a fascinating paper! It reveals a side of α-synuclein—an elusive neuron killer—which has escaped detection until now. This work may open a new chapter in the research of neurodegenerative diseases, namely, examining the role of lipids in preventing and/or promoting neural degeneration. Like all good work, this paper raises more questions than the answers it provides. Burning questions would include, for example, whether the accumulation of soluble oligomers to a certain level is sufficient for neural degeneration, or just a prelude for neural degeneration. If soluble oligomers just set the stage for neural degeneration, then it will be important to find out whether this is because soluble oligomers have to recruit additional factors or have to proceed to the stage of insoluble aggregates in order for neurons to die. We can be sure many interesting papers will follow this work!
The obvious conclusion of this important paper is that PUFAs (polyunsaturated fatty acids) induce oligomerization of α-synuclein into neurotoxic species. Another potential source of neurotoxicity caused by PUFA-α-synuclein oligomers is that they may sequester biologically active PUFAs away in the neuron, ultimately resulting in neuronal dysfunction. It should by noted that levels of biologically active PUFAs in neurons are already relatively low even though they are required for a battery of cellular functions, including cell signaling and gene expression. Therefore, the existence of highly soluble α-synuclein oligomers may be doubly toxic, when potential sequestration of biologically active PUFAs is added to the equation.