Cellular and Molecular Neurobiology
Author: Cayetana Arnaiz | email: cayetanarnaiz@gmail.com
Cayetana Arnaiz 1°, Carolina Facal 2°, Mariana Holubiec 3°, Julieta Bianchelli 1°, Melina González-Prinz 1°, Elena Avale 2°, Tomás Falzone 3°
1° IBioBA-MPSP-CONICET
2° INGEBI
3° IBioBA-MPSP-CONICET, IBCN
The AIS regulates action potential and acts as a selective barrier for axonal cargo. It presents specific structural features: MT fascicles, Ankyrin-G linkers, and enrichment of ion channels. Tau, a MT-associated protein highly expressed in neurons, acts as an axonal transport regulator. Changes in tau have been associated with AIS defects. However, the molecular mechanisms by which tau modulates the AIS remain unknown. My work focuses on elucidating how tau regulates the AIS. Using hippocampal neurons from hTau mice, and hiPSC-derived neurons, we performed tau conditional KD and regulated tau isoform production. We show that tau isoform production can affect AIS maturation, positioning, and AnkG enrichment in murine neurons. We characterized the maturation and positioning of the AIS in hiPSC neurons, and showed that the proportion of neurons with AIS increases over time, and the intensity of AnkG staining. We confirmed that hiPSC neurons produce 4R-tau after 37 days in vitro. Increasing the early endogenous production of 4R-tau leads to a significant increase in the percentage of neurons with AIS. Finally, the effect of tau KD on the transport of APP within the AIS was evaluated by live-imaging. We found that decreasing tau expression selectively affects the anterograde transport of cargo within the AIS. This work will provide knowledge on how tau modulates the AIS, which is essential for understanding potential pathological mechanisms associated with tauopathies.