Tunneling Nanotubes: structure/function characterization and role in prion-like spreading of neurodegenerative diseases – Neurotunn

Tunneling nanotubes (TNTs) are actin-based fine protrusions connecting cells in culture and represent a novel mechanism
of cell-to-cell communication. They have been implicated in many phenomena and diseases including spreading of
infection, cancer and neurodegeneration. However, the lack of specific markers impairs their identification in vivo, as well
as the assessment of their specific functions. Interestingly, in the last few years, other proteins such as tau (which
characteristically accumulates intracellularly in Alzheimer’s disease and other neurodegenerative diseases called
tauopathies), alpha-synuclein (which aggregates are involved in Parkinson’s disease and other synucleinopathies) and
huntigtin (which aggregates are intimately linked to Huntington’s disease) have been shown to adopt a prion-like behavior
and to undergo the same mechanism of conformational changes, and seeding. Furthermore recent experimental evidence
supports a prion-like mechanism for the spread of misfolded proteins associated to various neurodegenerative diseases. If
these findings are confirmed they might explain progression and continuous decline in brain functions observed in these
diseases. As neuropathological symptoms worsen with disease progression, knowledge gained into the mechanism of
spreading would allow stopping early-on disease progression.
We have recently shown that TNTs mediate both exogenous and endogenous prions transfer between infected and naïve
mouse neuronal cells and that HTTExon1 assemblies are found in TNTs between neurons in culture. We hypothesize that
the transfer of amyloidogenic protein aggregates between cells occurs through TNTs. Thus, molecules involved in TNT
formation could represent valuable “druggable” targets.
We propose to assess the mechanism of transfer of different forms of HTT and a-syn assemblies, and analyze the
intracellular routing and effects of these assemblies in challenged neurons. We will study the mechanisms of TNT
formation, identify specific markers and characterize the effect of a-syn/HTT aggregates transfer through TNTs. These
combined tasks and multiple and complementary approaches set up by the two partners will generate important
knowledge on the progression and cell to cell transmissibility of protein aggregates involved in Parkinson's and
Huntington's diseases. Furthermore this knowledge should have high potential to identify common features between
different dramatic neurodegenerative diseases and will be invaluable to the design of new drugs aimed to halt their
progression.