Alpha-Synuclein Cell-to-Cell Transfer and Seeding in Grafted Dopaminergic Neurons In Vivo

Abstract

Several people with Parkinson’s disease have been treated with intrastriatal grafts of fetal dopaminergic neurons. Following autopsy, 10–22 years after surgery, some of the grafted neurons contained Lewy bodies similar to those observed in the host brain. Numerous studies have attempted to explain these findings in cell and animal models. In cell culture, α-synuclein has been found to transfer from one cell to another, via mechanisms that include exosomal transport and endocytosis, and in certain cases seed aggregation in the recipient cell. In animal models, transfer of α-synuclein from host brain cells to grafted neurons has been shown, but the reported frequency of the event has been relatively low and little is known about the underlying mechanisms as well as the fate of the transferred α-synuclein. We now demonstrate frequent transfer of α-synuclein from a rat brain engineered to overexpress human α-synuclein to grafted dopaminergic neurons. Further, we show that this model can be used to explore mechanisms underlying cell-to-cell transfer of α-synuclein. Thus, we present evidence both for the involvement of endocytosis in α-synuclein uptake in viv o, and for seeding of aggregation of endogenous α-synuclein in the recipient neuron by the transferred α-synuclein. Finally, we show that, at least in a subset of the studied cells, the transmitted α-synuclein is sensitive to proteinase K. Our new model system could be used to test compounds that inhibit cell-to-cell transfer of α-synuclein and therefore might retard progression of Parkinson neuropathology.

Distinct higher-order α-synuclein oligomers induce intracellular aggregation

“…Certain forms of α-syn located in the extracellular environment can be internalized and induce endogeneous α-syn to selfaggregate [6,18,[46][47][48][49]. This may represent a mechanism for the spread of aggregated α-syn in the PD brain.…”

The pathology roadmap in Parkinson disease

“…106 In this model, α-synuclein fibrils in the extracellular space are taken up by neurons and these fibrils seed Lewy pathology; some subset of these fibrils are then released, spreading the pathology. Thus, α-synuclein fibrils behave in a prion-like way.…”

Catechol Tetrahydroisoquinolines Enhance a-Synuclein Aggregation and Specify the Neurotoxicity to Dopaminergic Neurons

“…For many neurodegenerative diseases including PD, it is a typical characteristic that protein aggregate from monomer to β-sheet-rich amyloid fibrils.α-syn, known as a central component of LBs, is a synaptic protein with the tendency of misfolding and aggregation [85]. Although α-syn was first discovered in patients with familial forms of PD and its A53T, E46K and A30P mutations had also been shown to be related to the familial form of PD [4,86], α-syn appeared to be a vital genetic factor of PD pathology both in familial and sporadic cases.…”