Tunneling Nanotubes : Reshaping connectivity and role in the spreading of neurodegenerative diseases

Tunneling nanotubes (TNTs) are actin-based cellular connections that allow the transport of different cellular components between cells. They were described for the first time in a cell line in culture almost 20 years ago, and now they are recognized as an important mechanism of cell-to-cell communication. Since their discovery, the structure and function of TNTs have been characterized in several cell types, including neurons and astrocytes. Under homeostatic conditions, TNTs transport different vesicular cargoes and entire organelles like mitochondria and lysosomes. However, they can be hijacked by different pathogens and amyloid proteins involved in neurodegenerative diseases, such as Parkinson´s (PD) Alzheimer’s (AD). We have previously demonstrated that both alpha-synuclein and Tau aggregates, respectively the hallmark of PD and AD, can be spread from one cell to another via TNTs. We have proposed that this is a key mechanism for the progression of the disease and for the spreading of the pathology to the whole brain. In my talk I will address the similarities and differences between TNT-mediated diffusion of these two types of aggregates, in order to identify common pathways leading to neurodegeneration. I will also touch upon our study assessing the molecular mechanism of TN formation, and finally assess the likelihood of TNT in vivo, specifically using a serial SEM connectome approach in the mouse brain. Our most recent data indicate that TNT-like connections are present in the developing brain. Our hypothesis is that TNTs precede synaptic connections and may be important for the establishment of mature neuronal networks while in the adult tissue they are induced by stressful and inflammatory stimuli.