Interfering with Tau N-terminal-dependent vesicle-binding reverts Tau-induced presynaptic deficits in fly neurons. Drosophila larvae used in (a–c) express UAS-TauΔN (R406W, V337M or P301L) under the D42-Gal4 motor neuron driver. (a) FRAP measurements of vesicle mobility within synaptic boutons. Fluoresence recovery (% of initial fluorescence) was plotted over time and fit with double-exponential curves. n=22 (R406W), 20 (ΔN_R406W, ΔN_V337M), 24 (ΔN_P301L) or 25 (Control) boutons (3–5 boutons per animal). (b) Synapto-pHluorin responses to stimulation at 10 Hz with the presence of bafilomycin. Fluorescence change ΔF at ratio to maximal ΔF (NH4Cl dequenching) was plotted over time during the stimulation. Two-way ANOVA, n=7 (R406W, ΔN_R406W, ΔN_V337M, ΔN_P301L),9 (Control) NMJs (animals). (c) Electrophysiological recordings of EJP amplitudes during stimulation at 10 Hz. Two-way ANOVA, n=7 (R406W, ΔN_R406W), 8 (ΔN_V337M, ΔN_P301L), or 9 (Control) NMJs (animals). (d–h) Transmission electron microscopy (TEM) of lamina sections of 9-day-old flies expressing UAS-Tau (WT, P301L or ΔN_P301L) under the late-onset retinal driver Rhodopsin1-Gal4 (Rh1). In control Rh1-Gal4/+ animals (d), six photoreceptor synaptic terminals (outlined in dashed white lines) are converged in a ‘cartridge’ (outlined in white line). Disrupted synaptic terminal organization and morphology are detected in Rh1>Tau_P301L (f) flies, whereas no obvious abnormalities at the synaptic terminals of Rh1>Tau_WT (e) and Rh1>TauΔN_P301L (g) flies. Scale bar, 1 μm. (h) Quantification of the synaptic terminal area based on the electromicrographs. One-way ANOVA, ***P=0.0001. n=5 animals per genotype. Data present mean±s.e.m.
Tau proteins are best known as the proteins that are stacked to form neuronal “tangles” in Alzheimer’s patients’ brains, but they also play a role in many other brain disorders such as Parkinson’s and Huntington’s disease. In healthy circumstances, tau proteins are connected to the cytoskeleton of nerve cells, where they support the cells’ structural stability. In the nerve cells of patients, however, tau is dislodged from the cytoskeleton and ultimately tangles together to form protein accumulations that disrupt the nerve cell’s functioning.
But even before these protein accumulations are formed, the dislodged tau impedes the communication between nerve cells. VIB’s research team has described a new mechanism for this in the journal Nature Communications. Professor Patrik Verstreken (VIB-KU Leuven) explains: “We have demonstrated that when mutant tau dislodges from the cytoskeleton, it mainly settles at the synapses of the nerve cells. This was not only the case in fruit flies and rats but also in the brain cells of human patients. Vesicles containing chemicals are released at these synapses, which serve as the means of communication between two different nerve cells. When tau settles at the synapse, it locks onto the vesicles, inhibiting synaptic transmission.”
These new insights are the result of a close collaboration between different laboratories at VIB, the universities of Leuven, Louvain-la-Neuve (both in Belgium), and Edinburgh (UK), and with researchers from Janssen Pharmaceutica. They pave the way for a possible treatment.
“Now that we know how tau inhibits synaptic transmission, we can look for ways to prevent it.” Patrik Verstreken already provided proof of principle: “If we stop tau from locking onto the vesicles in the nerve cells of rats and fruit flies, we can prevent the inhibition of synaptic transmission and also the death of nerve cells.” Further research should reveal whether this strategy will also be useful for patients.
http://www.vib.be/en/news/Pages/Tau-prevents-synaptic-transmission-at-early-stage-of-neurodegeneration.aspx https://www.nature.com/articles/ncomms15295
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