I recently saw Chris Dobson speak at MIT and he presented some compelling evidence that the toxic species across the board of neurodegenerative diseases is what he called the “secondary oligomer.”  His group used a FRET assay to visualize the formation of alpha synuclein amyloid (the protein implicated in Parkinson’s disease).  They found that from monomers, the proteins first formed low-FRET oligomers which were random, disorganized, and proteinase-K susceptible, and low in beta-sheet content.  Over the course of the next 35 hours these oligomers transformed into high FRET oligomers which were more compact, proteinase-K resistant, and high in B-sheet content.  These secondary oligomers then transformed into fibrils.

When neurons were then exposed to alpha synuclien  monomers, primary oligomers, secondary oligomers, and fibrils, the neurons took up the protein in all four forms — but the secondary oligomers were much more toxic to the neurons than any other form.

Dobson proposed intervention in the kinetics of the oligomer A to oligomer B conversion as  a therapeutic goal, especially given that this conversion takes time.  His lab has identified a compound which they call “484228″ which they think might be able to target this conversion in the case of Parkinson’s.  They are working with Elan Pharmaceuticals in SF to develop this compound as a therapeutic.

Another cool assay that he described, but that I found harder to follow, involved the direct observation of the initial steps in fibril formation by use of microfluidics.

According to Dobson, the toxic secondary oligomer is not a discrete, specific entity.  Rather, there are lots of different forms (he suggested about 20) that meet the criteria described above — high FRET, more compact, proteinase-K resistant, B-sheet rich, on the road to becoming amyloid.  This is in contrast to work recently published by David Eisenberg.  Eisenberg agrees that the oligomer is the toxic species, but has described one oligomeric structure in particular to fill this role.  Excitingly, this is the first toxic oligomer/intermediate species to be crystallized.  Here’s a link to the abstract — this paper was published in Science earlier this year: http://www.ncbi.nlm.nih.gov/pubmed/22403391

To add to the chorus of voices incriminating the oligomer, Susan Lindquist recently presented some autopsy images — sorry no citation for this — from the brains of cognitively highly-functioning adults who had died in accidents.  What made these brains remarkable was an extremely high level of amyloid, even though these people never showed symptoms of neurodegeneration.  A amyloid-as-toxic-species model would have predicted severe dementia when in fact they showed none at all.

A final person to mention in this vein is Charles Glabe, who apparently developed an antibody ten years ago — the A11 antibody — that recognized and bound to various oligomers from different neurodegenerative diseases — despite the different proteins having little or no sequence similarity.  What a mystery!  This suggested to him that the oligomers, if not the monomers or amyloid, had something in common across diseases — and that the mechanism of toxicity was likewise shared.  The paper was called “Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis,” published in Science in 2003.  http://www.sciencemag.org/content/300/5618/486.abstract