Alpha-synuclein gets around - secretion of synuclein oligomers

This afternoon PD researchers were aggregating like alpha-synuclein around one poster in particular: "Secreted alpha-synucelin oligomers - A new target for therapeutic intervention in Parkinson's disease?" After pushing my way to the front of the pack, I was able to listen to Dr. Karin Danzer, presenter and first author of the work, describe her findings in detail.

"We've been able to really detect oligomers, and this is new," Dr. Danzer proudly said. Using transfected constructs of synuclein fused to luciferase complimentary fragments, she and her colleagues could visualize oligomerization of synuclein secreted from neuronal cells. Upon dimerization of the proteins, luciferase activity would increase allowing her team to distinguish between the monomeric and oligomerized forms.

Looking more closely into the secretion of these oligomers, Dr. Danzer and her colleagues utilized an innovative microfluidic device, allowing a separation between neuronal cell bodies and axonal projections. Cells can be seeded in one side of the device and the axons grow across a small section terminating in a separate compartment, enabling not only isolation of where alpha synuclein is secreted (from axonal terminals) but also showing the uptake of alpha-synuclein in the axonal compartment and retrograde transport to the cell bodies. "We've shown real physiological consequences - alpha-synuclein is getting in and out," said Dr. Danzer, demonstrating transmission from neuron to neuron and neuron to glia. Additionally, alpha-synuclein staining also showed a punctate pattern - while not necessarily indicating Lewy body formation, this pattern may represent the initial formation of aggregates.

Taking the work a step further, Dr. Danzer then looked at mechanisms to regulate oligomer formation and toxicity. Overexpression of the molecular chaperone Hsp70 inhibited extracellular synuclein aggregation though didn't reduce synuclein levels, indicating Hsp70 may act as a chaperone in the extracellular space. The presence of Hsp70 in the media also prevented oligomer formation and reduced toxicity in cultured primary neurons. "The neighboring cells really suffer, and we can rescue the toxicity with Hsp70 or an Hsp90 inhibitor," Dr. Danzer explained.

Dr. Danzer and her collagues in Dr. Pam McLean's group show the secretion and uptake of alpha-synuclein oligomers in mature neurons and demonstrate a mechanism to rescue toxicity in primary neurons through molecular chaperones. This work is a beautiful addition to the published findings of alpha-synuclein transmission from Drs. Seung-Jae Lee and Eliezer Masliah and colleagues, and has recently been submitted for publication. Of course, a number of questions remain unanswered. Perhaps most importantly, does this uptake of alpha-synuclein lead to true Lewy body formation and pathology, and how can we investigate this in an in vivo model? Numerous functions and pathways are involved in the etiology of Parkinson's disease, and it remains to be seen how these findings contribute to PD pathogenesis and progression in vivo. As with most insights into alpha-synucelin pathology, the lack of a good PD model showing Lewy body formation and nigrostriatal dopaminergic cell death is a major roadblock to truly unraveling the tangled story of alpha-synuclein. However, as the authors suggest in their title, secreted oligomeric alpha-synuclein may be a key target for future therapeutic intervention.

Secreted alpha-synuclein oligomers - A new target for therapeutic intervention in Parkinson’s disease? K. M. DANZER, P. PUTCHA, T. HASHIMOTO, B. T. HYMAN, P. J. MCLEAN. Society for Neuroscience Annual Meeting 2009.