α-Synuclein aggregates (white puncta) being transferred from an aggregate-burdened neuron (left) to a microglial cell (right) through a tunneling nanotube.Ranabir Chakraborty and Chiara Zurzolo, Institut PasteurOne of the greatest debates in neuroscience go back to 1906, when Camillo Golgi and Santiago Ramón y Cajal argued their opposing views on brain structure.1 Golgi assumed that brain cells are physically connected and, as a result, the cells function as one entity. Conversely, Cajal hypothesized that each brain cell functions separately, however communicates with each other. While Cajals theory has actually formed the basis of neuroscience as we understand it, Golgis theory was not entirely incorrect. In 2004, Hans-Hermann Gerdes group from the University of Heidelberg found open-ended, membrane-enclosed channels between neuron-like cells, called tunning nanotubes (TNTs).2 However the discovery of TNTs has not gone without its own debate.” People didnt think these structures. They couldnt believe that cells would interact through tunnels. This breaks the dogma of the cell as a specific entity,” said Chiara Zurzolo, the head of the Membrane Traffic and Pathogenesis Unit at the Institut Pasteur. Years of research study later on, scientists have actually revealed that TNTs allow the exchange of ions, organelles, and protein aggregates in between a variety of cell types, such as astrocytes and nerve cells. While investigating if microglia, the resident immune cells of the brain, and neurons interact through TNTs, Zurzolo and her group uncovered a protective function for microglia in neurodegenerative illness and released these findings in Cell Death and Disease.3 Zurzolo ended up being interested in microglia due to the fact that they internalize and degrade poisonous protein aggregates and, therefore, can avoid the develop of aggregates within the brain. As aggregate build-up is particular of numerous neurodegenerative diseases such as Alzheimers disease and Parkinsons disease, and ultimately leads to neuronal death, this recommends that microglia protect the brain from neurodegeneration.4 However, microglia can likewise directly or indirectly cause neuronal death, which might intensify neurodegeneration. “Its not clear whether microglia are … helping with the development of these diseases or trying to block the progression … to conserve the neuron,” stated Zurzolo.In their newest research study, Chiara Zurzolo and Ranabir Chakraborty identified that tunneling nanotubes could form between microglia, as displayed on the computer system monitor, and between nerve cells and microglia.Valentine Thomas, Institut PasteurZurzolos team initially identified if functional TNTs form in between microglia and nerve cells. They treated a neuronal cell line with α-Synuclein (α-Syn), a protein typically aggregated in Parkinsons disease, and co-cultured the neurons with microglial cells. The team observed α-Syn aggregates moving from aggregate-burdened nerve cells to microglia, which they believe minimizes neuronal cell tension and likely licenses aggregate degradation by microglia.5 When microglia were exposed to α-Syn before the researchers co-cultured them with neurons, the majority of the burdened microglia did not move aggregates to the nerve cells, which recommended that microglia secure nerve cells from becoming exposed to aggregates.In addition to aggregate transfer, the researchers found another manner in which microglia assist α-Syn-burdened neurons. As aggregate build-up can result in mitochondrial damage in nerve cells, Zurzolos team examined if mitochondria are transferred from microglia to neurons through the TNTs. The group incubated neurons with α-Syn, identified mitochondria in microglial cells, and cultured the cells together. They discovered that mitochondria from microglia were preferentially transferred to unhealthy, aggregate-filled neurons over healthy nerve cells. Eventually, Zurzolo thinks this exchange between nerve cells and microglia can relieve the pressure positioned on unhealthy nerve cells by allowing the microglial-mediated damage of aggregates and providing the neurons with healthy mitochondria to get rid of the aggregate-mediated mitochondrial damage.For TNTs, we do not understand nearly anything … however because its brand-new … [its] a million times more amazing. — Chiara Zurzolo, Institut Pasteur” I believe [the research study] consolidates what we understand about microglia being crucial to eliminate harmful aggregates,” said Marie-Ève Tremblay, an associate teacher at the University of Victoria, who was not associated with the research study. “I think it fits with the general recognized functions of microglia while explaining the new methods by which these functions are attained.” Zurzolo is confident that more research study into TNTs can shed more light on the communication in between unhealthy and healthy cells in the brain, as well as the value of TNTs to advancement and aging. Furthermore, TNT-mediated interaction is relatively undiscovered in contrast to other intercellular communication mechanisms, consisting of receptor-mediated endocytosis, that makes additional insight into this system important. “For TNTs, we dont know practically anything … but since its brand-new … [its] a million times more interesting,” Zurzolo said.ReferencesZurzolo C. Tunneling nanotubes: Reshaping connectivity. Curr Opin Cell Biol. 2021; 71:139 -147. doi:10.1016/ j.ceb.2021.03.003 Rustom A, Saffrich R, Markovic I, Walther P, Gerdes HH. Nanotubular highways for intercellular organelle transport. Science. 2004; 303( 5660 ):1007 -1010. doi:10.1126/ science.1093133 Chakraborty R, Nonaka T, Hasegawa M, Zurzolo C. Tunnelling nanotubes between microglial and neuronal cells permit bi-directional transfer of α-Synuclein and mitochondria. Cell Death Dis. 2023; 14( 5 ):1 -12. doi:10.1038/ s41419-023-05835-8Menzies FM, Fleming A, Caricasole A, et al. Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. Neuron. 2017; 93( 5 ):1015 -1034. doi:10.1016/ j.neuron.2017.01.022 Scheiblich H, Dansokho C, Mercan D, et al. Microglia jointly degrade fibrillar alpha-synuclein freight by circulation through tunneling nanotubes. Cell. 2021; 184( 20 ):5089 -5106. e21. doi:10.1016/ j.cell.2021.09.007.
α-Synuclein aggregates (white puncta) being transferred from an aggregate-burdened nerve cell (left) to a microglial cell (right) through a tunneling nanotube.Ranabir Chakraborty and Chiara Zurzolo, Institut PasteurOne of the most significant controversies in neuroscience dates back to 1906, when Camillo Golgi and Santiago Ramón y Cajal argued their opposing views on brain structure.1 Golgi hypothesized that brain cells are physically linked and, consequently, the cells function as one entity. “Its not clear whether microglia are … assisting in the progression of these illness or trying to block the development … to conserve the neuron,” said Zurzolo.In their most current study, Chiara Zurzolo and Ranabir Chakraborty figured out that tunneling nanotubes might form in between microglia, as displayed on the computer system monitor, and between neurons and microglia.Valentine Thomas, Institut PasteurZurzolos team first determined if practical TNTs form between nerve cells and microglia. The team observed α-Syn aggregates moving from aggregate-burdened neurons to microglia, which they think decreases neuronal cell stress and likely permits aggregate degradation by microglia.5 When microglia were exposed to α-Syn before the scientists co-cultured them with neurons, the majority of the strained microglia did not move aggregates to the neurons, which suggested that microglia safeguard neurons from becoming exposed to aggregates.In addition to aggregate transfer, the scientists found another way that microglia help α-Syn-burdened nerve cells. As aggregate accumulation can result in mitochondrial damage in neurons, Zurzolos group assessed if mitochondria are moved from microglia to nerve cells through the TNTs. They found that mitochondria from microglia were preferentially moved to unhealthy, aggregate-filled neurons over healthy neurons.