Abstract
Parkinson’s disease (PD) is characterized by the presence of inclusions known as Lewy bodies, which mainly consist of α-synuclein (α-syn) aggregates. There is growing evidence that α-syn self-propagates in non-neuronal cells, thereby contributing to the progression and spread of PD pathology in the brain. Tunneling nanotubes (TNTs) are long, thin, F-actin-based membranous channels that connect cells and have been proposed to act as conduits for α-syn transfer between cells. SH-SY5Y cells and primary human brain pericytes, derived from postmortem PD brains, frequently form TNTs that allow α-syn transfer and long-distance electrical coupling between cells. Pericytes in situ contain α-syn precipitates like those seen in neurons. Exchange through TNTs was rapid, but dependent on the size of the protein. Proteins were able to spread throughout a network of cells connected by TNTs. Transfer through TNTs was not restricted to α-syn; fluorescent control proteins and labeled membrane were also exchanged through TNTs. Most importantly the formation of TNTs and transfer continued during mitosis. Together, our results provide a detailed description of TNTs in SH-SY5Y cells and human brain PD pericytes, demonstrating their role in α-syn transfer and further emphasize the importance that non-neuronal cells, such as pericytes play in disease progression.
Highlights
Parkinson’s disease (PD) is characterized by the presence of intracellular inclusions called Lewy bodies
Intrastriatal grafts from healthy embryonic dopaminergic neurons, given to PD patients, contained α-syn-positive Lewy bodies when the brain was autopsied more than 10 years later4,5. α-syn is not restricted to the central nervous system and is able to cross the blood-brain barrier in both directions[6], with α-syn and its phosphorylated form being present in human blood plasma[7]
We determined that SH-SY5Y cells and human primary brain pericytes use Tunneling nanotubes (TNTs) as a mechanism for intercellular α-syn transfer and show that TNTs provide for the transport of α-syn pathology
Summary
Irrespective of the cause of PD (genetic or sporadic) there is an accumulation and spread of α-syn, which leads to the pathology of the disease. Our findings suggest an additional mechanism explaining how α-syn pathology can spread throughout the brain Both SH-SY5Y cells and human brain pericytes frequently form TNTs that function as a conduit for α-syn transfer between cells and long-distance electrical coupling. The temporary increase in TNT numbers when cells go through mitosis might play an important role in α-syn transport, not necessarily between mature neurons, but because other replicating non-neuronal cell types (like the brain-derived pericytes used in this study) could play a role in vivo in the spread of α-syn. TNT-mediated transport is not restricted to α-syn or membrane exchange, but likely plays a more general role in cellular communication This manuscript provides further evidence that a-syn spread can be attributed to TNTs and that pericytes, a key non-neuronal cell type in the blood brain barrier, could be involved in this process. As a-syn spread is seen as a contributor to PD pathology, elucidating mechanisms of this transfer may offer additional therapeutic targets to conventional PD therapy
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